Indazoles, benzothiazoles, and benzoisothiazoles, and preparation and uses thereof

ABSTRACT

The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (indazoles and benzothiazoles), which act as ligands for the α7 nAChR subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.

[0001] This application claims the benefit of U.S. Provisionalapplication Serial No. 60/413,151, filed Sep. 25, 2002, and U.S.Provisional application Serial No. 60/448,469, filed Feb. 21, 2003, theentire disclosures of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates generally to the field of ligandsfor nicotinic acetylcholine receptors (nAChR), activation of nAChRs, andthe treatment of disease conditions associated with defective ormalfunctioning nicotinic acetylcholine receptors, especially of thebrain. Further, this invention relates to novel compounds, which act asligands for the α7 nAChR subtype, methods of preparing such compounds,compositions comprising such compounds, and methods of use thereof.

BACKGROUND OF THE INVENTION

[0003] There are two types of receptors for the neurotransmitter,acetylcholine: muscarinic receptors and nicotinic receptors, based onthe selectivity of action of muscarine and nicotine, respectively.Muscarinic receptors are G-protein coupled receptors. Nicotinicreceptors are members of the ligand-gated ion channel family. Whenactivated, the conductance of ions across the nicotinic ion channelsincreases.

[0004] Nicotinic alpha-7 receptor protein forms a homo-pentamericchannel in vitro that is highly permeable to a variety of cations (e.g.,Ca⁺⁺). Each nicotinic alpha-7 receptor has four transmembrane domains,named M1, M2, M3, and M4. The M2 domain has been suggested to form thewall lining the channel. Sequence alignment shows that nicotinic alpha-7is highly conserved during evolution. The M2 domain that lines thechannel is identical in protein sequence from chicken to human. Fordiscussions of the alpha-7 receptor, see, e.g., Revah et al. (1991),Nature, 353, 846-849; Galzi et al. (1992), Nature 359, 500-505; Fucileet al. (2000), PNAS 97(7), 3643-3648; Briggs et al. (1999), Eur. J.Pharmacol. 366 (2-3), 301-308; and Gopalakrishnan et al. (1995), Eur. JPharmacol. 290(3), 237-246.

[0005] The nicotinic alpha-7 receptor channel is expressed in variousbrain regions and is believed to be involved in many importantbiological processes in the central nervous system (CNS), includinglearning and memory. Nicotinic alpha-7 receptors are localized on bothpresynaptic and postsynaptic terminals and have been suggested to beinvolved in modulating synaptic transmission. It is therefore ofinterest to develop novel compounds, which act as ligands for the α7nAChR subtype, for the treatment of disease conditions associated withdefective or malfunctioning nicotinic acetylcholine receptors.

SUMMARY OF THE INVENTION

[0006] This invention relates to novel compounds, which act as ligandsfor the α7 nAChR subtype, methods of preparing such compounds,compositions comprising such compounds, and methods of use thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention includes compounds of Formulas I, II, III,or IV:

[0008] wherein

[0009] A is

[0010] X is O or S;

[0011] R¹ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃),cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃),cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7carbon atoms, alkylthio having 1 to 4 carbon atoms (e.g., SCH₃),fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF₃, OCHF₂),hydoxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Ar orHet;

[0012] R² is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms;

[0013] R³ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃),cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃),cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7carbon atoms, alkylthio having 1 to 4 carbon atoms (e.g., SCH₃),fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF₃, OCHF₂),hydoxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Ar orHet;

[0014] R⁴ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃),cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃),cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7carbon atoms, alkylthio having 1 to 4 carbon atoms (e.g., SCH₃),fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF₃, OCHF₂),hydoxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Ar orHet;

[0015] R⁵ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃),cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃),cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4 to 7carbon atoms, alkylthio having 1 to 4 carbon atoms (e.g., SCH₃),fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF₃, OCHF₂),hydoxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Ar orHet;

[0016] Ar is an aryl group containing 6 to 10 carbon atoms which isunsubstituted or substituted one or more times by alkyl having 1 to 8 Catoms, alkoxy having 1 to 8 C atoms, halogen (F, Cl, Br, or I,preferably F or Cl), dialkylamino wherein the alkyl portions each have 1to 8 C atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1to 8 C atoms, halogenated alkoxy having 1 to 8 C atoms, hydroxyalkylhaving 1 to 8 C atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxyhaving 3 to 8 C atoms, alkylthio having 1 to 8 C atoms, alkylsulphinylhaving 1 to 8 C atoms, alkylsulphonyl having 1 to 8 C atoms,monoalkylamino having 1 to 8 C atoms, cycloalkylamino wherein thecycloalkyl group has 3 to 7 C atoms and is optionally substituted,aryloxy wherein the aryl portion contains 6 to 10 carbon atoms (e.g.,phenyl, naphthyl, biphenyl) and is optionally substituted, arylthiowherein the aryl portion contains 6 to 10 carbon atoms (e.g., phenyl,naphthyl, biphenyl) and is optionally substituted, cycloalkyloxy whereinthe cycloalkyl group has 3 to 7 C atoms and is optionally substituted,sulfo, sulfonylamino, acylamido (e.g., acetamido), acyloxy (e.g.,acetoxy) or combinations thereof, and

[0017] Het is a heterocyclic group, which is fully saturated, partiallysaturated or fully unsaturated, having 5 to 10 ring atoms in which atleast 1 ring atom is a N, O or S atom, which is unsubstituted orsubstituted one or more times by halogen (F, Cl, Br, or I, preferably For Cl), aryl having 6 to 10 carbon atoms (e.g., phenyl, naphthyl,biphenyl) and is optionally substituted, alkyl having 1 to 8 C atoms,alkoxy having 1 to 8 C atoms, cyano, trifluoromethyl, nitro, oxo, amino,monoalkylamino having 1 to 8 C atoms, dialkylamino wherein each alkylgroup has 1 to 8 C atoms, or combinations thereof; and

[0018] pharmaceutically acceptable salts thereof.

[0019] In Formula I, when A is an indazolyl group of subformula (a), itis preferably attached to the remainder of the compound via its 3, 4 or7 position. When A is a benzothiazolyl group of subformula (b), it ispreferably attached to the remainder of the compound via its 4 or 7position. When A is a benzoisothiazolyl group of subformula (c), it ispreferably attached to the remainder of the compound via its 3, 4 or 7position.

[0020] Similarly, in Formula II, when A is an indazolyl group ofsubformula (a), it is preferably attached to the remainder of thecompound via its 3, 4 or 7 position. When A is a benzothiazolyl group ofsubformula (b), it is preferably attached to the remainder of thecompound via its 4 or 7 position. When A is a benzoisothiazolyl group ofsubformula (c), it is preferably attached to the remainder of thecompound via its 3, 4 or 7 position.

[0021] Also, in Formula III, when A is an indazolyl group of subformula(a), it is preferably attached to the remainder of the compound via its3, 4 or 7 position. When A is a benzothiazolyl group of subformula (b),it is preferably attached to the remainder of the compound via its 4 or7 position. When A is a benzoisothiazolyl group of subformula (c), it ispreferably attached to the remainder of the compound via its 3, 4 or 7position.

[0022] Further, in Formula IV, when A is an indazolyl group ofsubformula (a), it is preferably attached to the remainder of thecompound via its 3, 4 or 7 position. When A is a benzothiazolyl group ofsubformula (b), it is preferably attached to the remainder of thecompound via its 4 or 7 position. When A is a benzoisothiazolyl group ofsubformula (c), it is preferably attached to the remainder of thecompound via its 3, 4 or 7 position.

[0023] The present invention includes compounds of Formulas I′, II′,III′, or IV′:

[0024] wherein

[0025] A is

[0026] R′ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃),cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃),cycloalkoxy having 3 to 7 carbon atoms, alkylthio having 1 to 4 carbonatoms (e.g., SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,OCF₃, OCHF₂), hydoxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyhaving 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms,dialkylamino wherein each alkyl group independently has 1 to 4 carbonatoms, Ar or Het;

[0027] R² is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms;

[0028] R³ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, alkyl having I to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃),cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g., OCH₃),cycloalkoxy having 3 to 7 carbon atoms, alkylthio having 1 to 4 carbonatoms (e.g., SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms (e.g.,OCF₃, OCHF₂), hydoxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyhaving 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms,dialkylamino wherein each alkyl group independently has 1 to 4 carbonatoms, Ar or Het;

[0029] Ar is an aryl group containing 6 to 10 carbon atoms which isunsubstituted or substituted one or more times by alkyl having 1 to 8 Catoms, alkoxy having 1 to 8 C atoms, halogen (F, Cl, Br, or I,preferably F or Cl), dialkylamino wherein the alkyl portions each have 1to 8 C atoms, amino, cyano, hydroxyl, nitro, halogenated alkyl having 1to 8 C atoms, halogenated alkoxy having 1 to 8 C atoms, hydroxyalkylhaving 1 to 8 C atoms, hydroxyalkoxy having 2 to 8 C atoms, alkenyloxyhaving 3 to 8 C atoms, alkylthio having 1 to 8 C atoms, alkylsulphinylhaving 1 to 8 C atoms, alkylsulphonyl having 1 to 8 C atoms,monoalkylamino having 1 to 8 C atoms, cycloalkylamino wherein thecycloalkyl group has 3 to 7 C atoms and is optionally substituted,aryloxy wherein the aryl portion contains 6 to 10 carbon atoms (e.g.,phenyl, naphthyl, biphenyl) and is optionally substituted, arylthiowherein the aryl portion contains 6 to 10 carbon atoms (e.g., phenyl,naphthyl, biphenyl) and is optionally substituted, cycloalkyloxy whereinthe cycloalkyl group has 3 to 7 C atoms and is optionally substituted,sulfo, sulfonylamino, acylamido (e.g., acetamido), acyloxy (e.g.,acetoxy) or combinations thereof, and

[0030] Het is a heterocyclic group, which is fully saturated, partiallysaturated or fully unsaturated, having 5 to 10 ring atoms in which atleast 1 ring atom is a N, O or S atom, which is unsubstituted orsubstituted one or more times by halogen (F, Cl, Br, or I, preferably For Cl), aryl having 6 to 10 carbon atoms (e.g., phenyl, naphthyl,biphenyl) and is optionally substituted, alkyl having 1 to 8 C atoms,alkoxy having 1 to 8 C atoms, cyano, trifluoromethyl, nitro, oxo, amino,monoalkylamino having 1 to 8 C atoms, dialkylamino wherein each alkylgroup has 1 to 8 C atoms, or combinations thereof, and

[0031] pharmaceutically acceptable salts thereof.

[0032] In Formula I′, when A is an indazolyl group of subformula (a), itis preferably attached to the remainder of the compound via its 3, 4 or7 position. When A is a benzothiazolyl group of subformula (b), it ispreferably attached to the remainder of the compound via its 4 or 7position.

[0033] Similarly, in Formula II′, when A is an indazolyl group ofsubformula (a), it is preferably attached to the remainder of thecompound via its 3, 4 or 7 position. When A is a benzothiazolyl group ofsubformula (b), it is preferably attached to the remainder of thecompound via its 4 or 7 position.

[0034] Also, in Formula III′, when A is an indazolyl group of subformula(a), it is preferably attached to the remainder of the compound via its3, 4 or 7 position. When A is a benzothiazolyl group of subformula (b),it is preferably attached to the remainder of the compound via its 4 or7 position.

[0035] Further, in Formula IV′, when A is an indazolyl group ofsubformula (a), it is preferably attached to the remainder of thecompound via its 3, 4 or 7 position. When A is a benzothiazolyl group ofsubformula (b), it is preferably attached to the remainder of thecompound via its 4 or 7 position.

[0036] In Formulas I-IV and I′-IV′, the indazolyl, benzothiazolyl andbenzoisothiazolyl groups of A can be attached to the remainder of thestructure via any suitable attachment point. The following subformulasillustrate some of the preferred attachments between the indazole andbenzothiazole groups and the remainder of the structure.

[0037] The following subformulas further illustrate some of thepreferred attachments between the indazolyl, benzothiazolyl andbenzoisothiazolyl groups and the remainder of the structure.

[0038] The following subformulas further illustrate some of thepreferred attachments between the indazolyl, benzothiazolyl andbenzoisothiazolyl groups and the remainder of the structure.

[0039] The following subformulas further illustrate some of thepreferred attachments between the indazolyl, benzothiazolyl andbenzoisothiazolyl groups and the remainder of the structure.

[0040] In a more preferred embodiment, the following subformulasillustrate some of the more preferred attachments between the indazolyl,benzothiazolyl and benzoisothiazolyl groups and the remainder of thestructures of Formulas I and I′.

[0041] In accordance with a method aspect of the invention, there isprovided a method of treating a patient (e.g., a mammal such as a human)suffering from a disease state (e.g., memory impairment) comprisingadministering to the patient a compound according to Formulas I-IV orI′-IV′. Preferably, the disease state involves decreased nicotinicacetylcholine receptor activity.

[0042] In accordance with a method aspect of the invention there isprovided a method for the treatment or prophylaxis of a disease orcondition resulting from dysfunction of nicotinic acetylcholine receptortransmission in a mammal, e.g. a human, comprising administering aneffective amount of a compound according to Formulas I-IV or I′-IV′.

[0043] In accordance with a method aspect of the invention there isprovided a method for the treatment or prophylaxis of a disease orcondition resulting from defective or malfunctioning nicotinicacetylcholine receptors, particularly α7nACh receptors, in a mammal,e.g. a human, comprising administering an effective amount of a compoundaccording to Formulas I-IV or I′-IV′.

[0044] In accordance with a method aspect of the invention there isprovided a method for the treatment or prophylaxis of a disease orcondition resulting from suppressed nicotinic acetylcholine receptortransmission in a mammal, e.g., a human, comprising administering anamount of a compound according to Formulas I-IV or I′-IV′ effective toactivate α7nACh receptors.

[0045] In accordance with another method aspect of the invention thereis provided a method for the treatment or prophylaxis of a psychoticdisorder, a cognition impairment (e.g., memory impairment), orneurodegenerative disease in a mammal, e.g., a human, comprisingadministering an effective amount of a compound according to FormulasI-IV or I′-IV′.

[0046] In accordance with another method aspect of the invention thereis provided a method for the treatment or prophylaxis of a disease orcondition resulting from loss of cholinergic synapses in a mammal, e.g.,a human, comprising administering an effective amount of a compoundaccording to Formulas I-IV or I′-IV′.

[0047] In accordance with another method aspect of the invention thereis provided a method for the treatment or prophylaxis of aneurodegenerative disorder by activation of α7nACh receptors in amammal, e.g., a human, comprising administering an effective amount of acompound according to Formulas I-IV or I′-IV′.

[0048] In accordance with another method aspect of the invention thereis provided a method for protecting neurons in a mammal, e.g., a human,from neurotoxicity induced by activation of α7nACh receptors comprisingadministering an effective amount of a compound according to FormulasI-IV or I′-IV′.

[0049] In accordance with another method aspect of the invention thereis provided a method for the treatment or prophylaxis of aneurodegenerative disorder by inhibiting the binding of Aβ peptides toα7nACh receptors in a mammal, e.g., a human, comprising administering aneffective amount of a compound according to Formulas I-IV or I′-IV′.

[0050] In accordance with another method aspect of the invention thereis provided a method for protecting neurons in a mammal, e.g., a human,from neurotoxicity induced by Aβ peptides comprising administering aneffective amount of a compound according to Formulas I-IV or I′-IV′.

[0051] In accordance with another method aspect of the invention thereis provided a method for alleviating inhibition of cholinergic functioninduced by Aβ peptides in a mammal, e.g., a human, comprisingadministering an effective amount of a compound according to FormulasI-IV or I′-IV′.

[0052] The compounds of the present invention are nicotinic alpha-7ligands, preferably agonists, especially partial agonists, for thealpha-7 nicotinic acetylcholine receptor. Assays for determiningnicotinic acetylcholine activity are known within the art. See, e.g.,Davies, A. R., et al., Characterisation of the binding of[3H]methyllycaconitine: a new radioligand for labelling alpha 7-typeneuronal nicotinic acetylcholine receptors. Neuropharmacology, 1999.38(5): p. 679-90. As agonists for α-7 nAChRs, the compounds are usefulin the prophylaxis and treatment of a variety of diseases and conditionsassociated with the central nervous system. Nicotinic acetylcholinereceptors are ligand-gastrol ion-channel receptors that are composed offive subunit proteins which form a central ion-conducting pore.Presently, there are eleven known neuronal nAChR subunits (α2-α9 and β2-β4). There are also five further subunits expressed in the peripheralnervous system (α1, β1, γ, δ, ε).

[0053] The nAChR receptor subtypes can be homopentameric orheteropentameric. The subtype which has received considerable attentionis the homopentameric α7 receptor subtype formed from five α7 subunits.The α7nAChRs exhibit a high affinity for nicotine (agonist) and forα-bungarotoxin (antagonist). Studies have shown the α7-nAChR agonistscan be useful in the treatment of psychotic diseases, neurodegenerativediseases, and cognitive impairments, among other things. While nicotineis a known agonist, there is a need for the development of otherα7-nAChR agonists, especially selective agonists, that are less toxic orexhibit fewer side effects than nicotine.

[0054] The compound anabaseine, i.e.,2-(3-pyridyl)-3,4,5,6-tetrahydropyridine is a naturally occurring toxinin certain marine worms (nemertine worms) and ants. See, e.g., Kem etal., Toxicon, 9:23, 1971. Anabaseine is a potent activator of mammaliannicotinic receptors. See, e.g., Kem, Amer. Zoologist, 25, 99, 1985.Certain anabaseine analogs such as anabasine and DMAB(3-[4-(dimethylamino)benzylidene]-3,4,5,6-tetrahydro-2′,3′-bipyridine)are also known nicotinic receptor agonists. See, e.g., U.S. Pat. No.5,602,257 and WO 92/15306. One particular anabaseine analog,(E-3-[2,4-dimethoxy-benzylidene]-anabeseine, also known as GTS-21 andDMXB (see, e.g., U.S. Pat. No. 5,741,802), is a selective partialα7-nAChR agonist that has been studied extensively. For example,abnormal sensory inhibition is a sensory processing deficit inschizophrenics and GTS-21 has been found to increase sensory inhibitionthrough interaction with α7-nAChRs. See, e.g., Stevens et al.,Psychopharmacology, 136: 320-27 (1998).

[0055] Another compound which is known to be a selective α7-nAChRagonist is Tropisetron, i.e., 1αH, 5αH-tropan-3α-ylindole-3-carboxylate. See J. E. Macor et al., The 5-HT3-AntagonistTropisetron (ICS 205-930) is a Potent and Selective A7 NicotinicReceptor Partial Agonist. Bioorg. Med. Chem. Lett. 2001, 319-321).

[0056] Alkyl throughout means a straight-chain or branched-chainaliphatic hydrocarbon radical having preferably 1 to 4 carbon atoms.Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, and tert-butyl.

[0057] Alkoxy means alkyl-O- groups in which the alkyl portionpreferably has 1 to 4 carbon atoms. Suitable alkoxy groups includemethoxy, ethoxy, propoxy, isopropoxy, isobutoxy, and sec-butoxy.

[0058] Alkylthio means alkyl-S- groups in which the alkyl portionpreferably has 1 to 4 carbon atoms. Suitable alkylthio groups includemethylthio and ethylthio.

[0059] Cycloalkyl means a cyclic, bicyclic or tricyclic saturatedhydrocarbon radical having 3 to 7 carbon atoms. Suitable cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.Other suitable cycloalkyl groups include spiropentyl,bicyclo[2.1.0]pentyl, and bicyclo[3.1.0]hexyl.

[0060] Cycloalkoxy means cycloalkyl-O- groups in which the cycloalkylportion preferably is a cyclic, bicyclic or tricyclic saturatedhydrocarbon radical having 3 to 7 carbon atoms.

[0061] Cycloalkylalkyl groups contain 4 to 7 carbon atoms, for example,cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, andcyclopentylmethyl.

[0062] Cycloalkylalkoxy groups contain 4 to 7 carbon atoms, for example,cyclo-propylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, andcyclo-pentylmethyloxy.

[0063] The cycloalkyl and cycloalkylalkyl groups can be substituted byC₁₋₄-alkyl, C₁₋₄-alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4carbon atoms, and/or dialklyamino in which each alkyl group has 1 to 4carbon atoms.

[0064] Aryl, as a group or substituent per se or as part of a group orsubstituent, refers to an aromatic carbocyclic radical containing 6 to10 carbon atoms, unless indicated otherwise. Suitable aryl groupsinclude phenyl, napthyl and biphenyl. Substituted aryl groups includethe above-described aryl groups which are substituted one or more timesby halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl,hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio,alkylsulphinyl, alkylsulphonyl, phenoxy, and acyloxy (e.g., acetoxy).

[0065] Heterocyclic groups refer to saturated, partially saturated andfully unsaturated heterocyclic groups having one, two or three rings anda total number of 5 to 10 ring atoms wherein at least one of the ringatoms is an N, O or S atom. Preferably, the heterocyclic group contains1 to 3 hetero-ring atoms selected from N, O and S. Suitable saturatedand partially saturated heterocyclic groups include, but are not limitedto tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, isoxazolinyl and the like. Suitable heteroarylgroups include but are not limited to furyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl,isoquinolinyl, naphthyridinyl and the like. Other examples of suitableheterocyclic groups, are 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl,2-benzofuranyl, 2-benzothiophenyl, 3-thienyl,2,3-dihydro-5-benzofuranyl, 4-indoyl, 4-pyridyl, 3-quinolinyl,4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl, 2-pyrrolyl,3,4-1,2-benzopyran-6-yl, 5-indolyl, 1,5-benzoxepin-8-yl, 3-pyridyl,6-coumarinyl, 5-benzofuranyl, 2-isoimidazol-4-yl, 3-pyrazolyl, and3-carbazolyl.

[0066] Substituted heterocyclic groups refer to the heterocyclic groupsdescribed above, which are substituted in one or more places by, forexample, halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro,oxo, amino, alkylamino, and dialkylamino.

[0067] Radicals which are substituted one or more times preferably have1 to 3 substituents, especially 1 or 2 substituents of the exemplifiedsubstituents. Halogenated radicals such as halogenated alkyls arepreferably fluorinated and include perhalo radicals such astrifluoromethyl.

[0068] In the compounds of Formulas I-IV and I′-IV′, R¹ is preferably H,F, Cl, Br, methyl, methoxy, or amino, R² is preferably H or methyl, andR³ is preferably H, F, Cl, Br, methyl, methoxy, or amino.

[0069] Also, in the compounds of Formulas I-IV and I′-IV′, R¹ ispreferably H, F, Cl, Br, 2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl,R² is preferably H, methyl 2-thiophenyl, 3-thiophenyl, 3-furyl, orphenyl, and R³ is preferably H, F, Cl, Br, 2-thiophenyl, 3-thiophenyl,3-furyl, or phenyl.

[0070] Also, in the compounds of Formulas I-IV, R⁴ is preferably H, F,Cl, Br, 2-thiophenyl, 3-thiophenyl, 3-furyl, phenyl, or methoxy.

[0071] Also, in the compounds of Formulas I-IV, R⁵ is preferably H.

[0072] According to a compound aspect of the invention, the compound offormulas I-IV is selected from:

[0073] N-(1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamide,

[0074] N-(1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamidehydrochloride,

[0075]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamide,

[0076]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamidehydrochloride,

[0077] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamide,

[0078]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamidehydrochloride,

[0079] N-(1-Azabicyclo [2.2.2]oct-3-yl)-1H-indazole-3-carboxamide,

[0080] N-(-1-Azabicyclo[2.2.2]oct-3-yl)-1 H-indazole-3-carboxamidehydrochloride,

[0081] N-((3R)-1-Azabicyclo[2.2.2]oct-3 -yl)-1H-indazole-3 -carboxamide,

[0082] N-((3R)-1-Azabicyclo[2.2.2]oct-3 -yl)-1H-indazole-3-carboxamidehydrochloride,

[0083] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide,

[0084] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamidehydrochloride,

[0085] 1-Methyl-1H-Indazole-3-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0086] (R) 1-Methyl-1H-Indazole-3-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0087] (S) 1-Methyl-1H-Indazole-3-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0088]N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzo[d]isothiazole-3-carboxamide,

[0089] N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(methoxy)benzo[d]isothiazole-3-carboxamide hydroformate,

[0090]N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide,

[0091] N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(cyclopropyl)-1H-indazole-3-carboxamide hydroformate,

[0092] N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamidehydroformate,

[0093] N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamidehydroformate,

[0094] N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide,

[0095] N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate,

[0096] N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate,

[0097]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzo[d]isothiazole-3-carboxamide,

[0098]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(methoxy)benzo[d]isothiazole-3-carboxamidehydroformate,

[0099]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide,

[0100]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(cyclopropyl)-1H-indazole-3-carboxamidehydroformate,

[0101] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamide hydroformate,

[0102]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-H-indazole-3-carboxamidehydroformate,

[0103]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide,

[0104]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate,

[0105]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate,

[0106]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzo[d]isothiazole-3-carboxamide,

[0107]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-methoxybenzo[d]isothiazole-3-carboxamidehydroformate,

[0108] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-lH-indazole-3-carboxamide,

[0109]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamidehydroformate,

[0110] N-((3S)-1-Azabicyclo[2.2.2]oct-3 -yl)-5-(phenyl)-1H-indazole-3-carboxamide hydroformate,

[0111]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate,

[0112]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate,

[0113]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamide,

[0114]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-cyclopropylbenzo[d]isothiazole-3-carboxamide,

[0115]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamide,

[0116]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0117]N-((1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamide,

[0118] N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamide hydroformate,

[0119]N-((1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamide,

[0120]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0121] N-((1 -Azabicyclo[2.2.2]oct-3-yl)-6-(3-furan-3-yl)benzo[d]isothiazole-3 -carboxamide,

[0122] N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-furan-3-yl)benzo[d]isothiazole-3-carboxamide hydroformate,

[0123] N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxybenzo[d]isothiazole-3-carboxamide,

[0124]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(morpholin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0125]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamide,

[0126]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamidehydroformate,

[0127]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamide,

[0128]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0129]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamide,

[0130]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0131]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)benzo[d]isothiazole-3-carboxamide,

[0132]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)benzo[d]isothiazole-3-carboxamide,

[0133] N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(bromo)-1H-indazole-3-carboxamide,

[0134] N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3 -yl)- 1 H-indazole-3-carboxamide hydroformate,

[0135] N-((1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamide hydroformate,

[0136]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate,

[0137]N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate,

[0138]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamide,

[0139]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-cyclopropylbenzo[d]isothiazole-3-carboxamide,

[0140]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamide,

[0141]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0142]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamide,

[0143]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0144]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamide,

[0145]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0146]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-furan-3-yl)benzo[d]isothiazole-3-carboxamide,

[0147] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-furan-3-yl)benzo[d]isothiazole-3-carboxamide hydroformate,

[0148] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxybenzo[d]isothiazole-3 -carboxamide,

[0149] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(morpholin-4-yl)benzo[d]isothiazole-3 -carboxamide hydroformate,

[0150]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamide,

[0151]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamidehydroformate,

[0152]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamide,

[0153]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0154]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamide,

[0155] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamide hydroformate,

[0156]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)benzo[d]isothiazole-3-carboxamide,

[0157] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)benzo[d]isothiazole-3-carboxamide,

[0158] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(bromo)-1H-indazole-3-carboxamide,

[0159]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)-1H-indazole-3-carboxamidehydrofornate,

[0160] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamide hydrofornate,

[0161]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamidehydrofornate,

[0162] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamide hydroformate,

[0163]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamide,

[0164]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-cyclopropylbenzo[d]isothiazole-3-carboxamide,

[0165]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0166]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0167]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamide hydroformate,

[0168]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0169]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxybenzo[d]isothiazole-3-carboxamide,

[0170]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(morpholin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0171]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamide hydroformate,

[0172] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamide hydroformate,

[0173]5N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0174] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)benzo[d]isothiazole-3-carboxamide hydroformate,

[0175] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)benzo[d]isothiazole-3 -10 carboxamide,

[0176]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(bromo)-1H-indazole-3-carboxamide,

[0177] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)-1H-indazole-3-carboxamide hydroformate,

[0178]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamidehydroformate,

[0179] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3 -carboxamide hydroformate,

[0180]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate,

[0181] N-(1-Azabicyclo[2.2.2]oct-3-yl)-7-methoxybenzo[d]isothiazole-3-carboxamide,

[0182]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-7-methoxybenzo[d]isothiazole-3-carboxamide,

[0183]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-7-methoxybenzo[d]isothiazole-3-carboxamide,

[0184] N-(1-Azabicyclo[2,2,2]oct-3-yl)-N-(1 H-indazol-3-ylmethyl)amine,

[0185]N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)-N-(1H-indazol-3-ylmethyl)amine,

[0186] N-((3S)-1-Aza-bicyclo[2,2,2]oct-3-yl)-N-(1H-indazol-3-ylmethyl)amine,

[0187] N-(1-Aza-bicyclo[2.2.2]oct-3-yl)benzothiazole-4-carboxamidedihydrochloride,

[0188] N-((3R)-1-Aza-bicyclo[2.2.2]oct-3-yl)benzothiazole-4-carboxamidedihydrochloride,

[0189] N-((3S)-1-Aza-bicyclo[2.2.2]oct-3-yl)benzothiazole-4-carboxamidedihydrochloride,

[0190] N-(1 -Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-4-carboxamide,

[0191] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-4-carboxamide,

[0192] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-4-carboxamide,

[0193] N-(1H-Indazol-4-yl)- 1-azabicyclo[2,2,2]oct-3-ylcarboxamide,

[0194] N-(1-Azabicyclo[2,2,2]oct-3-yl)-N-(1 H-indazol-4-ylmethyl)amine,

[0195] N-(1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-5-carboxamide,

[0196] N-(1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-5-carboxamidehydrochloride,

[0197] N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-5-carboxamide,

[0198] N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-5-carboxamidehydrochloride,

[0199] N-((3S)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-5-carboxamide,

[0200] N-((3S)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-5-carboxamidehydrochloride,

[0201] N-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-5-carboxamide,

[0202] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-5-carboxamide,

[0203] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-5-carboxamide,

[0204] N-(1H-Indazol-5-yl)-1-aza-bicyclo[2.2.2]oct-3-ylcarboxamide,

[0205] N-(1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-6-carboxamide,

[0206] N-(1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-6-carboxamidehydrochloride,

[0207] N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-6-carboxamide,

[0208] N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-6-carboxamidehydrochloride,

[0209] N-((3S)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-6-carboxamidehydrochloride,

[0210] N-((3S)-1-Aza-bicyclo[2.2.2]oct-3-yl)benzothiazole-6-carboxamide,

[0211]N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)-2-pyrrol-1-ylbenzothiazole-6-carboxamidehydroformate,

[0212] N-(Benzothiazol-6-yl)-1-Azabicyclo[2,2,2]oct-3-ylcarboxamide,

[0213] N-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-6-carboxamide,

[0214] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-6-carboxamide,

[0215] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-6-carboxamide,

[0216] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-3-(thiophen-3-yl)-1H-indazole-6-carboxamide hydroformate,

[0217] N-(1H-Indazol-6-yl)-1-Azabicyclo[2,2,2]oct-3-ylcarboxamide,

[0218] N-(1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-7-carboxamidehydrochloride,

[0219] N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-7-carboxamidehydrochloride,

[0220] N-((3S)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-7-carboxamidehydrochloride,

[0221] N-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamide,

[0222] N-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamidehydrochloride,

[0223] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamide,

[0224] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamidehydrochloride,

[0225] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamide,

[0226] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamidehydrochloride,

[0227] Benzothiazole-4-carboxamide, N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0228] (R) Benzothiazole-4-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0229] (S) Benzothiazole-4-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0230] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-i H-indazol-3-yl,

[0231] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-3-yl,

[0232] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-3-yl,

[0233] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-4-yl,

[0234] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-4-yl,

[0235] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-4-yl,

[0236] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-5-yl,

[0237] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-5-yl,

[0238] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-5-yl,

[0239] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-6-yl,

[0240] (S)1-Aza-bicyclo[2,2,2]oct-3 -ylcarboxamide, N-1H-indazol-6-yl,

[0241] (R)1-Aza-bicyclo[2,2,2]oct-3 -ylcarboxamide, N-1H-indazol-6-yl,

[0242] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N1H-indazol-7-yl,

[0243] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-7-yl,

[0244] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-7-yl,

[0245] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-4-yl,

[0246] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-4-yl,

[0247] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-4-yl,

[0248] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-5-yl,

[0249] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-5-yl,

[0250] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-5-yl,

[0251] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-6-yl,

[0252] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-6-yl,

[0253] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-6-yl,

[0254] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-7-yl,

[0255] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-7-yl,

[0256] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-7-yl,

[0257] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-3-ylmethyl)-amine,

[0258] (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-3-ylmethyl)-amine,

[0259] (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-3-ylmethyl)-amine,

[0260] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-4-ylmethyl)-amine,

[0261] (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-4-ylmethyl)-amine,

[0262] (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-4-ylmethyl)-amine,

[0263] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-5-ylmethyl)-amine,

[0264] (S) (1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-5-ylmethyl)-amine,

[0265] (R) (1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-5-ylmethyl)-amine,

[0266] (1-Aza-bicyclo[2,2,2]oct-3 -yl)-(1H-indazol-6-ylmethyl)-amine,

[0267] (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-6-ylmethyl)-amine,

[0268] (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-6-ylmethyl)-amine,

[0269] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-7-ylmethyl)-amine,

[0270] (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-7-ylmethyl)-amine,

[0271] (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-7-ylmethyl)-amine,

[0272] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-4-ylmethyl)-amine,

[0273](S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-4-ylmethyl)-amine,

[0274](R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-4-ylmethyl)-amine,

[0275] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-5-ylmethyl)-amine,

[0276](S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-5-ylmethyl)-amine,

[0277](R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-5-ylmethyl)-amine,

[0278] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-6-ylmethyl)-amine,

[0279](S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-6-ylmethyl)-amine,

[0280](R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-6-ylmethyl)-amine,

[0281] (1-Aza-bicyclo[2,2,2]oct-3 -yl)-(benzothiazol-7-ylmethyl)-amine,

[0282](S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-7-ylmethyl)-amine,

[0283](R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-7-ylmethyl)-amine,

[0284] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-3-yl)-amine,

[0285] (S)(1 -Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-3-yl)-amine,

[0286] (R)(1 -Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-3-yl)-amine,

[0287] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-4-yl)-amine,

[0288] (S) (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-4-yl)-amine,

[0289] (R) (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-4-yl)-amine,

[0290] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-5-yl)-amine,

[0291] (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-5-yl)-amine,

[0292] (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-5-yl)-amine,

[0293] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-6-yl)-amine,

[0294] (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-6-yl)-amine,

[0295] (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-6-yl)-amine,

[0296] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-7-yl)-amine,

[0297] (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-7-yl)-amine,

[0298] (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-7-yl)-amine,

[0299] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-4-yl)-amine,

[0300] (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-4-yl)-amine,

[0301] (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-4-yl)-amine,

[0302] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-5-yl)-amine,

[0303](S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-5-yl)-amine,

[0304](R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-5-yl)-amine,

[0305] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-6-yl)-amine,

[0306](S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-6-yl)-amine,

[0307](R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-6-yl)-amine,

[0308] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-7-yl)-amine,

[0309](S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-7-yl)-amine,

[0310](R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-7-yl)-amine, andphysiological salts thereof.

[0311] According to another preferred compound aspect of the invention,the compound of formulas I-IV is selected from:

[0312]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamide,

[0313]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamidehydrochloride,

[0314] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamide,

[0315]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamidehydrochloride,

[0316] N-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide,

[0317] N-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamidehydrochloride,

[0318] N-((3R)-1 -Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3 -carboxamide,

[0319] N-((3R)-1 -Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamidehydrochloride,

[0320] N-((3S)-1 -Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide,

[0321] N-((3S)-1 -Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamidehydrochloride,

[0322] 1-Methyl-1H-Indazole-3-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0323] (R)1-Methyl-1H-Indazole-3-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0324] (S)1-Methyl-1H-Indazole-3-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0325]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzo[d]isothiazole-3-carboxamide,

[0326]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(methoxy)benzo[d]isothiazole-3-carboxamidehydroformate,

[0327]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide,

[0328]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(cyclopropyl)-1H-indazole-3-carboxamidehydroformate,

[0329]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamidehydroformate,

[0330]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamidehydroformate,

[0331]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide,

[0332]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate,

[0333]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate,

[0334]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzo[d]isothiazole-3-carboxamide,

[0335]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-methoxybenzo[d]isothiazole-3-carboxamidehydroformate,

[0336] N-((3S)-1-Azabicyclo[2.2.2]oct-3 -yl)-5-(bromo)-1H-indazole-3-carboxamide,

[0337] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3 -carboxamide hydroformate,

[0338]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamidehydroformate,

[0339]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate,

[0340]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate,

[0341]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamide,

[0342]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-cyclopropylbenzo[d]isothiazole-3-carboxamide,

[0343]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamide,

[0344]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0345]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamide,

[0346]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0347]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamide,

[0348] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3 -carboxamide hydroformate,

[0349]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-furan-3-yl)benzo[d]isothiazole-3-carboxamide,

[0350]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-furan-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0351]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxybenzo[d]isothiazole-3-carboxamide,

[0352] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(morpholin-4-yl)benzo[d]isothiazole-3 -carboxamide hydroformate,

[0353]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamide,

[0354]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamide hydroformate,

[0355]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamide,

[0356]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0357]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamide,

[0358]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0359] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)benzo[d]isothiazole-3-carboxamide,

[0360] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)benzo[d]isothiazole-3-carboxamide,

[0361] N-((3R)-1-Azabicyclo[2.2.2]oct-3 -yl)-6-(bromo)-1H-indazole-3-carboxamide,

[0362] N-((3R)-1-Azabicyclo[2.2.2]oct-3 -yl)-6-(furan-3-yl)-1H-indazole-3 -carboxamide hydroformate,

[0363] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamide hydroformate,

[0364] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamide hydroformate,

[0365] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamide hydroformate,

[0366]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamide,

[0367]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-cyclopropylbenzo[d]isothiazole-3-carboxamide,

[0368]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0369] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0370] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0371]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0372]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxybenzo[d]isothiazole-3-carboxamide,

[0373]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(morpholin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0374]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamidehydroformate,

[0375]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0376]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate,

[0377]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)benzo[d]isothiazole-3-carboxamide hydroformate,

[0378]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)benzo[d]isothiazole-3-carboxamide,

[0379] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(bromo)-1H-indazole-3-carboxamide,

[0380] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)-1H-indazole-3-carboxamide hydroformate,

[0381]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamidehydroformate,

[0382]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate,

[0383]N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamide hydroformate,

[0384]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-7-methoxybenzo[d]isothiazole-3-carboxamide,

[0385] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-7-methoxybenzo[d]isothiazole-3 -carboxamide,

[0386]N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)-N-(1H-indazol-3-ylmethyl)amine,

[0387]N-((3S)-1-Aza-bicyclo[2,2,2]oct-3-yl)-N-(1H-indazol-3-ylmethyl)amine,

[0388] N-((3R)-1-Aza-bicyclo[2.2.2]oct-3-yl)benzothiazole-4-carboxamidedihydrochloride,

[0389] N-((3S)-1-Aza-bicyclo[2.2.2]oct-3-yl)benzothiazole-4-carboxamidedihydrochloride,

[0390] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-4-carboxamide,

[0391] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-4-carboxamide,

[0392] N-(1H-Indazol-4-yl)-1-azabicyclo[2,2,2]oct-3 -ylcarboxamide,

[0393] N-(1-Azabicyclo[2,2,2]oct-3-yl)-N-(1H-indazol-4-ylmethyl)amine,

[0394] N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-7-carboxamidehydrochloride,

[0395] N-((3S)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-7-carboxamidehydrochloride,

[0396] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamide,

[0397] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamidehydrochloride,

[0398] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamide,

[0399] N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamidehydrochloride,

[0400] Benzothiazole-4-carboxamide, N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0401] (R)Benzothiazole-4-carboxamide, N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0402] (S)Benzothiazole-4-carboxamide, N-1-aza-bicyclo[2,2,2]oct-3-yl,

[0403] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-3-yl,

[0404] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-3-yl,

[0405] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-3-yl,

[0406] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-4-yl,

[0407] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-4-yl,

[0408] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-7-yl,

[0409] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-7-yl,

[0410] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, N-1H-indazol-7-yl,

[0411] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-4-yl,

[0412] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-4-yl,

[0413] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-4-yl,

[0414] 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-7-yl,

[0415] (S)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-7-yl,

[0416] (R)1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide, benzothiazol-7-yl,

[0417] (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-3-ylmethyl)-amine,

[0418] (R)(1-Aza-bicyclo[2,2,2]oct-3 -yl)-(1H-indazol-3-ylmethyl)-amine,

[0419] (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-4-ylmethyl)-amine,

[0420] (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-4-ylmethyl)-amine,

[0421] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-5-ylmethyl)-amine,

[0422] (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-5-ylmethyl)-amine,

[0423] (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-5-ylmethyl)-amine,

[0424] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-6-ylmethyl)-amine,

[0425] (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-6-ylmethyl)-amine,

[0426] (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-6-ylmethyl)-amine,

[0427] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-7-ylmethyl)-amine,

[0428] (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-7-ylmethyl)-amine,

[0429] (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-7-ylmethyl)-amine,

[0430] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-4-ylmethyl)-amine,

[0431](S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-4-ylmethyl)-amine,

[0432](R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-4-ylmethyl)-amine,

[0433] (1-Aza-bicyclo[2,2,2]oct-3 -yl)-(benzothiazol-5-ylmethyl)-amine,

[0434](S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-5-ylmethyl)-amine,

[0435](R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-5-ylmethyl)-amine,

[0436] (1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-6-ylmethyl)-amine,

[0437](S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-6-ylmethyl)-amine,

[0438](R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-6-ylmethyl)-amine,

[0439] (1-Aza-bicyclo[2,2,2]oct-3 -yl)-(benzothiazol-7-ylmethyl)-amine,

[0440](S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-7-ylmethyl)-amine,

[0441](R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-7-ylmethyl)-amine,

[0442] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-3-yl)-amine,

[0443] (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-3-yl)-amine,

[0444] (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-3-yl)-amine,

[0445] (1-Aza-bicyclo[2,2,2]oct-3 -ylmethyl)-(1H-indazol-4-yl)-amine,

[0446] (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-4-yl)-amine,

[0447] (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-4-yl)-amine,

[0448] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-5-yl)-amine,

[0449] (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-5-yl)-amine,

[0450] (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-5-yl)-amine,

[0451] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-6-yl)-amine,

[0452] (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-6-yl)-amine,

[0453] (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-6-yl)-amine,

[0454] (1-Aza-bicyclo[2,2,2]oct-3 -ylmethyl)-(1H-indazol-7-yl)-amine,

[0455] (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-7-yl)-amine,

[0456] (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-( 1H-indazol-7-yl)-amine,

[0457] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-4-yl)-amine,

[0458](S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-4-yl)-amine,

[0459](R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-4-yl)-amine,

[0460] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-5-yl)-amine,

[0461](S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-5-yl)-amine,

[0462](R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-5-yl)-amine,

[0463] (1-Aza-bicyclo[2,2,2]oct-3 -ylmethyl)-(benzothiazol-6-yl)-amine,

[0464](S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-6-yl)-amine,

[0465](R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-6-yl)-amine,

[0466] (1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-7-yl)-amine,

[0467](S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-7-yl)-amine,

[0468](R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-7-yl)-amine, andphysiological salts thereof.

[0469] Preferred aspects include pharmaceutical compositions comprisinga compound of this invention and a pharmaceutically acceptable carrierand, optionally, another active agent as discussed below; a method ofstimulating or activating inhibiting alpha-7 nicotinic receptors, e.g.,as determined by a conventional assay or one described herein, either invitro or in vivo (in an animal, e.g., in an animal model, or in a mammalor in a human); a method of treating a neurological syndrome, e.g., lossof memory, especially long-term memory, cognitive impairment or decline,memory impairment, etc. method of treating a disease state modulated bynicotinic alpha-7 activity, in a mammal, e.g., a human, e.g., thosementioned herein.

[0470] The compounds of the present invention may be preparedconventionally. Some of the known processes that can be used aredescribed below. All starting materials are known or can beconventionally prepared from known starting materials.

[0471] Acids that can be used in the preparation of the quinuclidineamide are commercially available, can be prepared by known proceduresdescribed in the literature, or as described below. For example,indazolecarboxylic acids can be prepared from bromo-2-methylaniline bydiazotization followed by metal-halogen exchange and trapping with CO₂,to give the corresponding indazolecarboxylic acid (See, e.g., DeLucca,G. V. Substituted 2H-1,3-Diazapin-2-one Useful as an HIV ProteaseInhibitor, U.S. Pat. No. 6,313,110 B1, Nov. 6, 2001; and Sun, J. H.;Teleha, C. A.; Yan, J. S.; Rodgers, J. D.; Nugiel, D. A. EfficientSynthesis of 5-(Bromomethyl)- and 5-(Aminomethyl)-1-THP-Indazole. J.Org. Chem. 1997, 62, 5627-5629). 4-Benzothiazolecarboxylic acid can beprepared from 2-amino-4-chloro-benzothiazole by reaction with isoamylnitrite followed by metal-halogen exchange and trapping with CO₂.5-Benzothiazolecarboxylic acid can be prepared from4-chloro-3-nitrobenzoic acid by reaction with Na₂S and NaOH followed byreduction with Zn in formic acid. 3-Aminoquinuclidine and the R- andS-enantiomers thereof are commercially available. The quinuclidine amidecan be prepared by the coupling reaction of acids with3-aminoquinuclidine and HBTU or HOBt and EDCI in DMF, or by convertingthe acids to the corresponding acid chloride and then reacting with3-aminoquinuclidine (Macor, J. E.; Gurley, D.; Lanthorn, T.; Loch, J.;Mack, R. A.; Mullen, G.; Tran, O.; Wright, N.; and J. E. Macor et al.,The 5-HT3-Antagonist Tropisetron (ICS 205-930) is a Potent and Selectiveα-7 Nicotinic Receptor Partial Agonist. Bioorg. Med. Chem. Lett. 2001,9, 319-321). The couplings are generally performed at room temperaturesfor 4-8 hours. Thioamide analogs can be prepared from the amides byreaction with Lawesson's reagent (Wipf P.; Kim, Y.; Goldstein, D. M., J.Am. Chem. Soc., 1995, 117, 11106). The resultant adducts can be isolatedand purified by standard techniques, such as chromatography orrecrystallization, practiced by those skilled in the art.

[0472] Quinuclidine amines may be prepared from quinuclidine amides bystandard reduction procedures as described, for example, below.

[0473] One of ordinary skill in the art will recognize that compounds ofFormulas I-IV and I′-IV′ can exist in different tautomeric andgeometrical isomeric forms. All of these compounds, including cisisomers, trans isomers, diastereomic mixtures, racemates, nonracemicmixtures of enantiomers, substantially pure, and pure enantiomers, arewithin the scope of the present invention. Substantially pureenantiomers contain no more than 5% w/w of the corresponding oppositeenantiomer, preferably no more than 2%, most preferably no more than 1%.

[0474] The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, dibenzoyltartaric,ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomerscan be separated into their individual diastereomers on the basis oftheir physical and/or chemical differences by methods known to thoseskilled in the art, for example, by chromatography or fractionalcrystallization. The optically active bases or acids are then liberatedfrom the separated diastereomeric salts. A different process forseparation of optical isomers involves the use of chiral chromatography(e.g., chiral HPLC columns), with or without conventional derivation,optimally chosen to maximize the separation of the enantiomers. Suitablechiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD andChiracel OJ among many others, all routinely selectable. Enzymaticseparations, with or without derivitization, are also useful. Theoptically active compounds of Formulas I-IV and I′-IV′ can likewise beobtained by utilizing optically active starting materials in chiralsynthesis processes under reaction conditions which do not causeracemization.

[0475] In addition, one of ordinary skill in the art will recognize thatthe compounds can be used in different enriched isotopic forms, e.g.,enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C. In oneparticular embodiment, the compounds are deuterated. Such deuteratedforms can be made the procedure described in U.S. Pat. Nos. 5,846,514and 6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997,deuteration can improve the efficacy and increase the duration of actionof drugs.

[0476] Deuterium substituted compounds can be synthesized using variousmethods such as described in: Dean, Dennis C.; Editor. Recent Advancesin the Synthesis and Applications of Radiolabeled Compounds for DrugDiscovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] (2000),110 pp. CAN 133:68895 AN 2000:473538 CAPLUS; Kabalka, George W.; Varma,Rajender S. The synthesis of radiolabeled compounds via organometallicintermediates. Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRABISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E.Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem.(1981), 64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN1981:476229 CAPLUS.

[0477] Where applicable, the present invention also relates to usefulforms of the compounds as disclosed herein, such as pharmaceuticallyacceptable salts or prodrugs of all the compounds of the presentinvention for which salts or prodrugs can be prepared. Pharmaceuticallyacceptable salts include those obtained by reacting the main compound,functioning as a base, with an inorganic or organic acid to form a salt,for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid,methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid,succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid,tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonicacid. Pharmaceutically acceptable salts also include those in which themain compound functions as an acid and is reacted with an appropriatebase to form, e.g., sodium, potassium, calcium, magnesium, ammonium, andcholine salts. Those skilled in the art will further recognize that acidaddition salts of the claimed compounds may be prepared by reaction ofthe compounds with the appropriate inorganic or organic acid via any ofa number of known methods. Alternatively, alkali and alkaline earthmetal salts can be prepared by reacting the compounds of the inventionwith the appropriate base via a variety of known methods.

[0478] The following are further examples of acid salts that can beobtained by reaction with inorganic or organic acids: acetates,adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates,bisulfates, butyrates, camphorates, digluconates,cyclopentanepropionates, dodecylsulfates, ethanesulfonates,glucoheptanoates, glycerophosphates, hemisulfates, heptanoates,hexanoates, fumarates, hydrobromides, hydroiodides,2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates,nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates,persulfates, 3-phenylpropionates, picrates, pivalates, propionates,succinates, tartrates, thiocyanates, tosylates, mesylates andundecanoates.

[0479] Preferably, the salts formed are pharmaceutically acceptable foradministration to mammals. However, pharmaceutically unacceptable saltsof the compounds are suitable as intermediates, for example, forisolating the compound as a salt and then converting the salt back tothe free base compound by treatment with an alkaline reagent. The freebase can then, if desired, be converted to a pharmaceutically acceptableacid addition salt.

[0480] The compounds of the invention can be administered alone or as anactive ingredient of a formulation. Thus, the present invention alsoincludes pharmaceutical compositions of compounds of Formulas I-IV andI′-IV′, containing, for example, one or more pharmaceutically acceptablecarriers.

[0481] Numerous standard references are available that describeprocedures for preparing various formulations suitable for administeringthe compounds according to the invention. Examples of potentialformulations and preparations are contained, for example, in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (current edition); Pharmaceutical Dosage Forms: Tablets(Lieberman, Lachman and Schwartz, editors) current edition, published byMarcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences(Arthur Osol, editor), 1553-1593 (current edition).

[0482] In view of their alpha-7 stimulating activity and, preferablytheir high degree of selectivity, the compounds of the present inventioncan be administered to anyone needing stimulation of alpha-7 receptors.Administration may be accomplished according to patient needs, forexample, orally, nasally, parenterally (subcutaneously, intraveneously,intramuscularly, intrastemally and by infusion) by inhalation, rectally,vaginally, topically and by ocular administration.

[0483] Various solid oral dosage forms can be used for administeringcompounds of the invention including such solid forms as tablets,gelcaps, capsules, caplets, granules, lozenges and bulk powders. Thecompounds of the present invention can be administered alone or combinedwith various pharmaceutically acceptable carriers, diluents (such assucrose, mannitol, lactose, starches) and excipients known in the art,including but not limited to suspending agents, solubilizers, bufferingagents, binders, disintegrants, preservatives, colorants, flavorants,lubricants and the like. Time release capsules, tablets and gels arealso advantageous in administering the compounds of the presentinvention.

[0484] Various liquid oral dosage forms can also be used foradministering compounds of the inventions, including aqueous andnon-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Suchdosage forms can also contain suitable inert diluents known in the artsuch as water and suitable excipients known in the art such aspreservatives, wetting agents, sweeteners, flavorants, as well as agentsfor emulsifying and/or suspending the compounds of the invention. Thecompounds of the present invention may be injected, for example,intravenously, in the form of an isotonic sterile solution. Otherpreparations are also possible.

[0485] Suppositories for rectal administration of the compounds of thepresent invention can be prepared by mixing the compound with a suitableexcipient such as cocoa butter, salicylates and polyethylene glycols.Formulations for vaginal administration can be in the form of a pessary,tampon, cream, gel, paste, foam, or spray formula containing, inaddition to the active ingredient, such suitable carriers as are knownin the art.

[0486] For topical administration the pharmaceutical composition can bein the form of creams, ointments, liniments, lotions, emulsions,suspensions, gels, solutions, pastes, powders, sprays, and dropssuitable for administration to the skin, eye, ear or nose. Topicaladministration may also involve transdermal administration via meanssuch as transdermal patches.

[0487] Aerosol formulations suitable for administering via inhalationalso can be made. For example, for treatment of disorders of therespiratory tract, the compounds according to the invention can beadministered by inhalation in the form of a powder (e.g., micronized) orin the form of atomized solutions or suspensions. The aerosolformulation can be placed into a pressurized acceptable propellant.

[0488] The compounds can be administered as the sole active agent or incombination with other pharmaceutical agents such as other agents usedin the treatment of cognitive impairment and/or memory loss, e.g., otherα-7 agonists, PDE4 inhibitors, calcium channel blockers, muscarinic m1and m2 modulators, adenosine receptor modulators, amphakines NMDA-Rmodulators, mGluR modulators, dopamine modulators, serotonin modulators,canabinoid modulators, and cholinesterase inhibitors (e.g., donepezil,rivastigimine, and glanthanamine). In such combinations, each activeingredient can be administered either in accordance with their usualdosage range or a dose below their usual dosage range.

[0489] The compounds of the invention can be used in conjunction with“positive modulators” which enhance the efficacy of nicotinic receptoragonists. See, e.g., the positive modulators disclosed in WO 99/56745,WO 01/32619, and WO 01/32622. Such combinational therapy can be used intreating conditions/diseases associated with reduced nicotinictransmission.

[0490] Further the compounds may be used in conjunction with compoundsthat bind to Aβ peptides and thereby inhibit the binding of the peptidesto α7nAChr subtypes. See, e.g., WO 99/62505.

[0491] The present invention further includes methods of treatment thatinvolve activation of α-7 nicotinic receptors. Thus, the presentinvention includes methods of selectively activating/stimulating α-7nicotinic receptors in animals, e.g., mammals, especially humans,wherein such activation/stimulation has a therapeutic effect, such aswhere such activation may relieve conditions involving neurologicalsyndromes, such as the loss of memory, especially long-term memory. Suchmethods comprise administering to an animal in need thereof, especiallya mammal, most especially a human, an effective amount of a compound ofFormulas I-IV or I′-IV′, alone or as part of a formulation, as disclosedherein.

[0492] Agents that bind to nicotinic acetylcholine receptors have beenindicated as useful in the treatment and/or prophylaxis of variousdiseases and conditions, particularly psychotic diseases,neurodegenerative diseases involving a dysfunction of the cholinergicsystem, and conditions of memory and/or cognition impairment, including,for example, schizophrenia, anxiety, mania, depression, manic depression[examples of psychotic disorders], Tourette's syndrome, Parkinson'sdisease, Huntington's disease [examples of neurodegenerative diseases],cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia,Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognitiondeficit, attention deficit, Attention Deficit Hyperactivity Disorder),and other uses such as treatment of nicotine addiction, inducing smokingcessation, treating pain (i.e., analgesic use), providingneuroprotection, and treating jetlag. See, e.g., WO 97/30998; WO99/03850; WO 00/42044; WO 01/36417; Holladay et al., J.Med. Chem.,40:26, 4169-94 (1997); Schmitt et al., Annual Reports Med. Chem.,Chapter 5, 41-51 (2000); Stevens et al., Psychopharmatology, (1998) 136:320-27 (1998); and Shytle et al., Molecular Psychiatry, (2002), 7, pp.525-535.

[0493] Thus, in accordance with the invention, there is provided amethod of treating a patient, especially a human, suffering frompsychotic diseases, neurodegenerative diseases involving a dysfunctionof the cholinergic system, and conditions of memory and/or cognitionimpairment, including, for example, schizophrenia, anxiety, mania,depression, manic depression [examples of psychotic disorders],Tourette's syndrome, Parkinson's disease, Huntington's disease [examplesof neurodegenerative diseases], and/or cognitive disorders (such asAlzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis,memory impairment, memory loss, cognition deficit, attention deficit,Attention Deficit Hyperactivity Disorder) comprising administering tothe patient an effective amount of a compound according to Formulas I-IVor I′-IV′.

[0494] Neurodegenerative disorders included within the methods of thepresent invention include, but are not limited to, treatment and/orprophylaxis of Alzheimer's diseases, Pick's disease, diffuse Lewy Bodydisease, progressive supranuclear palsy (Steel-Richardson syndrome),multisystem degeneration (Shy-Drager syndrome), motor neuron diseasesincluding amyotrophic lateral sclerosis, degenerative ataxias, corticalbasal degeneration, ALS-Parkinson's-Dementia complex of Guam, subacutesclerosing panencephalitis, Huntington's disease, Parkinson's disease,synucleinopathies, primary progressive aphasia, striatonigraldegeneration, Machado-Joseph disease/spinocerebellar ataxia type 3,olivopontocerebellar degenerations, Gilles De La Tourette's disease,bulbar, pseudobulbar palsy, spinal muscular atrophy, spinobulbarmuscular atrophy (Kennedy's disease), primary lateral sclerosis,familial spastic paraplegia, Werdnig-Hoffmann disease,Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease,familial spastic disease, Wohlfart-Kugelberg-Welander disease, spasticparaparesis, progressive multifocal leukoencephalopathy, prion diseases(such as Creutzfeldt-Jakob, Gerstmann-Sträussler-Scheinker disease, Kuruand fatal familial insomnia), and neurodegenerative disorders resultingfrom cerebral ischemia or infarction including embolic occlusion andthrombotic occlusion as well as intracranial hemorrhage of any type(including, but not limited to, epidural, subdural, subarachnoid andintracerebral), and intracranial and intravertebral lesions (including,but not limited to, contusion, penetration, shear, compression andlaceration).

[0495] In addition, α-7nAChRs agonists, such as the compounds of thepresent invention can be used to treat age-related dementia and otherdementias and conditions with memory loss including age-related memoryloss, senility, vascular dementia, diffuse white matter disease(Binswanger's disease), dementia of endocrine or metabolic origin,dementia of head trauma and diffuse brain damage, dementia pugilisticaand frontal lobe dementia. See, e.g., WO 99/62505. Thus, in accordancewith the invention, there is provided a method of treating a patient,especially a human, suffering from age-related dementia and otherdementias and conditions with memory loss comprising administering tothe patient an effective amount of a compound according to Formulas I-IVor I′-IV′.

[0496] Thus, in accordance with a further embodiment, the presentinvention includes methods of treating patients suffering from memoryimpairment due to, for example, mild cognitive impairment due to aging,Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeld-Jakob disease, depression, aging,head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarctdementia and other neurological conditions, as well as HIV andcardiovascular diseases, comprising administering an effective amount ofa compound according to Formulas I-IV or I′-IV′.

[0497] Amyloid precursor protein (APP) and AP peptides derivedtherefrom, e.g., Aβ₁₋₄₀, Aβ₁₋₄₂, and other fragments, are known to beinvolved in the pathology of Alzhemier's disease. The Aβ₁₋₄₂ peptidesare not only implicated in neurotoxicity but also are known to inhibitcholinergic transmitter function. Further, it has been determined thatAβ peptides bind to α-7 nAChRs. Thus, agents which block the binding ofthe Aβ peptides to α-7 nAChRs are useful for treating neurodegenerativediseases. See, e.g., WO 99/62505. In addition, stimulation α-7 nAChRscan protect neurons against cytotoxicity associated with Aβ peptides.See, e.g., Kihara, T. et al., Ann. Neurol., 1997, 42, 159.

[0498] Thus, in accordance with an embodiment of the invention there isprovided a method of treating and/or preventing dementia in anAlzheimer's patient which comprises administering to the subject atherapeutically effective amount of a compound according to FormulasI-IV or I′-IV′ to inhibit the binding of an amyloid beta peptide(preferably, Aβ₁₋₄₂) with nAChRs, preferable α-7 nAChRs, mostpreferably, human α-7 nAChRs (as well as a method for treating and/orpreventing other clinical manifestations of Alzheimer's disease thatinclude, but are not limited to, cognitive and language deficits,apraxias, depression, delusions and other neuropsychiatric symptoms andsigns, and movement and gait abnormalities).

[0499] The present invention also provides methods for treating otheramyloidosis diseases, for example, hereditary cerebral angiopathy,nonneuropathic hereditary amyloid, Down's syndrome, macroglobulinemia,secondary familial Mediterranean fever, Muckle-Wells syndrome, multiplemyeloma, pancreatic- and cardiac-related amyloidosis, chronichemodialysis anthropathy, and Finnish and Iowa amyloidosis.

[0500] In addition, nicotinic receptors have been implicated as playinga role in the body's response to alcohol ingestion. Thus, agonists forα-7nAChR's can be used in the treatment of alcohol withdrawal and inanti-intoxication therapy. Thus, in accordance with an embodiment of theinvention there is provided a method of treating a patient for alcoholwithdrawal or treating a patient with anti-intoxication therapycomprising administering to the patient an effective amount of acompound according to Formulas I-IV or I′-IV′.

[0501] Agonists for the α-7nAChR subtypes can also be used forneuroprotection against damage associated with strokes and ischemia andglutamate-induced excitotoxicity. Thus, in accordance with an embodimentof the invention there is provided a method of treating a patient toprovide for neuroprotection against damage associated with strokes andischemia and glutamate-induced excitotoxicity comprising administeringto the patient an effective amount of a compound according to FormulasI-IV or I′-IV′.

[0502] As noted above, agonists for the α-7nAChR subtypes can also beused in the treatment of nicotine addiction, inducing smoking cessation,treating pain, and treating jetlag, obesity, diabetes, and inflammation.Thus, in accordance with an embodiment of the invention there isprovided a method of treating a patient suffering from nicotineaddiction, pain, jetlag, obesity and/or diabetes, or a method ofinducing smoking cessation in a patient comprising administering to thepatient an effective amount of a compound according to Formulas I-IV orI′-IV′.

[0503] In addition, due to their affinity to α-7nAChR's, labeledderivatives of the compounds of Formulas I-IV and I′-IV′ (e.g., C¹¹ orF¹⁸ labelled derivatives), can be used in neuroimaging of the receptorswithin, e.g., the brain. Thus, using such labeled agents in vivo imagingof the receptors can be performed using, e.g., PET imaging.

[0504] The condition of memory impairment is manifested by impairment ofthe ability to learn new information and/or the inability to recallpreviously learned information. Memory impairment is a primary symptomof dementia and can also be a symptom associated with such diseases asAlzheimer's disease, schizophrenia, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovasculardisease, and head trauma as well as age-related cognitive decline.

[0505] Thus, in accordance with an embodiment of the invention there isprovided a method of treating a patient suffering from, for example,mild cognitive impairment (MCI), vascular dementia (VaD), age-associatedcognitive decline (AACD), amnesia associated w/open-heart-surgery,cardiac arrest, and/or general anesthesia, memory deficits from earlyexposure of anesthetic agents, sleep deprivation induced cognitiveimpairment, chronic fatigue syndrome, narcolepsy, AIDS-related dementia,epilepsy-related cognitive impairment, Down's syndrome, Alcoholismrelated dementia, drug/substance induced memory impairments, DementiaPuglistica (Boxer Syndrome), and animal dementia (e.g., dogs, cats,horses, etc.) patient comprising administering to the patient aneffective amount of a compound according to Formulas I-IV or I′-IV′.

[0506] The dosages of the compounds of the present invention depend upona variety of factors including the particular syndrome to be treated,the severity of the symptoms, the route of administration, the frequencyof the dosage interval, the particular compound utilized, the efficacy,toxicology profile, pharmacokinetic profile of the compound, and thepresence of any deleterious side-effects, among other considerations.

[0507] The compounds of the invention can be administered to mammals,particularly humans, at typical dosage levels customary for α-7nicotinic receptor agonists such as the known α-7 nicotinic receptoragonist compounds mentioned above. For example, the compounds can beadministered, in single or multiple doses, by oral administration at adosage level of, for example, 0.0001-10 mg/kg/day, e.g., 0.01-10mg/kg/day. Unit dosage forms can contain, for example, 1-200 mg ofactive compound. For intravenous administration, the compounds can beadministered, in single or multiple dosages.

[0508] In carrying out the procedures of the present invention it is ofcourse to be understood that reference to particular buffers, media,reagents, cells, culture conditions and the like are not intended to belimiting, but are to be read so as to include all related materials thatone of ordinary skill in the art would recognize as being of interest orvalue in the particular context in which that discussion is presented.For example, it is often possible to substitute one buffer system orculture medium for another and still achieve similar, if not identical,results. Those of skill in the art will have sufficient knowledge ofsuch systems and methodologies so as to be able, without undueexperimentation, to make such substitutions as will optimally servetheir purposes in using the methods and procedures disclosed herein.

[0509] The present invention will now be further described by way of thefollowing non-limiting examples. In applying the disclosure of theseexamples, it should be kept clearly in mind that other and differentembodiments of the methods disclosed according to the present inventionwill no doubt suggest themselves to those of skill in the relevant art.

[0510] In the foregoing and in the following examples, all temperaturesare set forth uncorrected in degrees Celsius; and, unless otherwiseindicated, all parts and percentages are by weight.

[0511] The entire disclosures of all applications, patents andpublications, cited above and below, including U.S. provisional patentapplication Serial No. 60/413,151, filed Sep. 25, 2002, and U.S.Provisional application Serial No. 60/448,469, filed Feb. 21, 2003, arehereby incorporated by reference.

EXAMPLES

[0512] All spectra were recorded at 300 MHz on a Bruker Instruments NMRunless otherwise stated. Coupling constants (J) are in Hertz (Hz) andpeaks are listed relative to TMS (δ 0.00 ppm). Microwave reactions wereperformed using a Personal Chemistry Optimizer™ microwave reactor in 2.5mL or 5 mL Personal Chemistry microwave reactor vials. All reactionswere performed at 200° C. for 600 s with the fixed hold time ON unlessotherwise stated. Sulfonic acid ion exchange resins (SCX) were purchasedfrom Varian Technologies. Analytical HPLC was performed on 4.6 mm×100 mmXterra RP18 3.5μ columns using a gradient of 20/80 to 80/20 water (0.1%formic acid)/acetonitrile (0.1% formic acid) over 6 min.

[0513] Representative Procedures.

[0514] Procedure A

[0515] Procedure A provides a method for the coupling between3-aminoquinuclidine and carboxylic acids to form carboxamidederivatives.

[0516] To a solution of the carboxylic acid (16.1 mmol) inN,N-dimethylformamide (65 mL) was added HBTU (16.1 mmol), catalyticamount of dimethylaminopyridine, NAN-diisopropylethylamine (96.6 mmol)and 4 Å activated molecular sieves (2.6 g). The reaction mixture wasmaintained at room temperature for 2 h under nitrogen and then3-aminoquinuclidine dihydrochloride (16.1 mmol) was added. After 18 h,the solvent was removed under reduced pressure. The oily residue waspartitioned between saturated, aqueous sodium bicarbonate (25 mL) anddichloromethane (100 mL). The aqueous layer was further extracted with9/1 dichloromethane/methanol (5×100 mL) and the combined organic layerswere concentrated. The residue was purified by chromatography usingeither a mixture of 90/10/1 dichloromethane/methanol/ammonium hydroxideor 70/30/1 ethyl acetate/methanol/ammonium hydroxide as the eluent toprovide the product in 30%-70% yield. Alternatively, the products werepurified by preparative HPLC using an 8 min gradient of 95/5 to 20/80water (0.1% formic acid)/acetonitrile (0.1% formic acid).

[0517] Procedure B

[0518] Procedure B provides a method for the coupling between3-aminoquinuclidine and benzisothiazole carboxylic acids to formcarboxamide derivatives.

[0519] To a solution of 6-methoxybenzisothiazole-3-carboxylic acid (61mg, 0.30 mmol) in a 5/1 mixture of terahydrofuran/N,N-dimethylformamide(12 mL) was added diisopropylethylamine (0.2 mL, 1.1 mmol) and (115 mg,0.6 mmol) 3-(R)-aminoquinuclidine dihydrochloride. The mixture wascooled to 0° C., and HATU (115 mg, 0.3 mmol) was added in one portion.The reaction mixture was allowed to warm to rt and was maintainedovernight. The mixture was partitioned between saturated aqueouspotassium carbonate solution and a 95/5 mixture ofdichloromethane/methanol. The aqueous layer was extracted with 95/5dichloromethane/methanol (2X), and the combined organic layers werewashed with brine and dried over sodium sulfate. The crude product waspurified by chromatography (90/10/1 dichloromethane/methanol/ammoniumhydroxide) to provide 72 mg (75%) of the amide as a colorless solid.

[0520] Procedure C

[0521] Procedure C provides a method for the coupling between3-aminoquinuclidine and carboxylic acids to form carboxamidederivatives.

[0522] The coupling reaction and purification was performed according toprocedure A (indazoles, benzthiazoles) or according to procedure B(benzisothiazoles). The free base was dissolved in methanol (3.5 mL/mmolstarting acid) and treated with 1N hydrochloric acid in ether (3.5mL/mmol starting acid). The resulting suspension was diluted with ether(7 mL/mmol starting acid) and was maintained at room temperature for 2h. The solids were collected by filtration, rinsed with ether, and driedunder vacuum to yield (40-60%) of the salt.

[0523] Procedure D

[0524] Procedure D provides a method for the coupling between3-aminoquinuclidine and carboxylic acids to form carboxamidederivatives.

[0525] To a solution of the carboxylic acid (4.77 mmol) inN,N-dimethylformamide (14 mL) was added N,N-diisopropylethylamine (19mmol) and 3-aminoquinuclidine dihydrochloride (4.29 mmol). The reactionmixture was maintained at room temperature for 30 min under nitrogen andthen HATU (4.76 mol) was added. After 18 h, the reaction mixture wasfiltered through Celite (methanol rinse) and was divided equally amongst3 SCX columns. The columns were washed with methanol (100 mL each) andthe basic components were eluted with 2 M ammonia in methanol (100 mLeach) and concentrated. The residue was purified by chromatography [1/1to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammoniumhydroxide)] thus providing the product in 15%-50% yield.

[0526] Procedure E

[0527] Procedure E provides a method for the formation of carboxamidederivatives from methyl 3-quinuclidinecarboxylic acid ester.

[0528] To a solution of the amine in toluene was added 1.0 M solution oftrimethylaluminum in toluene (1.1 eq) at 0° C. After 30 min, anadditional 1.1 eq of trimethylaluminum was added followed by a solutionof methyl 3-quinuclidinecarboxylic acid ester hydrochloride salt (1.1eq) in dioxane (5 mL). The reaction mixture was heated at 70° C. for 10h, allowed to cool to rt, and was poured onto a cold, (0° C.) aqueoussolution of sodium bicarbonate. The aqueous layer was extracted with 5%methanol in methylene chloride (2×30 mL) and the combined organic layerswere washed with brine and concentrated. The residue was purified bypreparative HPLC using an 8 min gradient of 95/5 to 20/80 water (0.1%formic acid)/acetonitrile (0.1% formic acid).

[0529] Procedure F

[0530] Procedure F provides a method for the reduction of thecarboxamide to form secondary amie derivatives.

[0531] To a solution of the amide (50 mg) in tetrahydrofuran (4 mL) wasadded lithium aluminum hydride (4.0 eq). The reaction mixture was heatedat reflux for 4 h, was cooled to 0° C., and was cautiously quenched withethanol. The resultant slurry was poured onto ice water and extractedwith 5% methanol in dichloromethane (3×) and the combined organic layerswere concentrated. The residue was purified by preparative HPLC using an8 min gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile(0.1% formic acid).

[0532] Procedure G

[0533] Procedure G provides a method for the coupling between3-aminoquinuclidine and carboxaldehydes to form secondary aminederivatives.

[0534] The suspension of 1H-indazole-4-carboxaldehyde (100 mg),3-aminoquinuclidine dihydrocloride salt (1.0 eq), and 4 Å molecularsieves in dioxane (4 mL) was heated at reflux for 4 h. The reactionmixture was allowed to cool to rt and was treated with sodiumtriacetoxyborohydride (3 eq). The reaction mixture was maintained at rtfor 2 h and was poured into water, extracted with 5% methanol indichloromethane (2×30 mL), and the combined extracts were concentrated.The residue was purified by preparative HPLC using an 8 min gradient of95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid).

[0535] Procedure H

[0536] Procedure H provides a method for the coupling between brominatedand iodinated aminoquinuclidinecarboxamides and boronic acids to formaryl-substituted derivatives. In a 5 mL microwave reaction vessel wasadded the bromide (0.286 mmol), the boronic acid (0.588 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.0289 mmol),tri-tert-butylphosphine tetrafluoroborate (0.0579 mmol), and potassiumcarbonate (0.810 mmol). The vessel was evacuated, back-filled with argongas, and the contents diluted with N,N-dimethylformamide (5.0 mL). Thevessel was sealed and subjected to microwave irradiation at 200° C. for600 s. The contents of the reaction were filtered through Celite(methanol wash) and loaded on a 5 g SCX column. The column was washedwith methanol (50 mL) and the product was eluted with 2 M ammonia inmethanol and concentrated. The residue was purified by preparative HPLCusing an 8 min gradient of 95/5 to 20/80 water (0.1% formicacid)/acetonitrile (0.1% formic acid) to give 15-40% of the product

[0537] Procedure I

[0538] Procedure I provides a method for the coupling between brominated3-aminoquinuclidinecarboxamides and amines to form amino-substitutedderivatives.

[0539] In a 5 mL microwave reaction vessel was addedN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzo[d]isothiazole-3-carboxamide(133 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium (0) (34 mg,0.04 mmol), caesium bicarbonate (213 mg, 1.1 mmol), and(2′-dicyclohexylphosphanylbiphenyl-2-yl)dimethylamine (30 mg, 0.07mmol). The vial was then evacuated and back-filled with argon gas. Themixture of solids was then diluted with morpholine (0.7 mL), dioxane (1mL), and triethylamine (0.5 mL) and the reaction vessel was sealed. Thereaction mixture was subjected to microwave irradiation at 120° C. for1800 s. The reaction mixture was filtered through a plug of celite andconcentrated in vacuo. The crude product was purified by chromatography(90/10/1 dichloromethane/methanol/ammonium hydroxide) to provide 47 mg(34%) of 6-morpholin-4-ylbenzo[d]isothiazole-3-carboxylic acid((3R)-1-azabicyclo[2.2.2]oct-3-yl)amide as a colorless solid.

[0540] Procedure J

[0541] Procedure J provides a method for the coupling between brominated3-aminoquinuclidinecarboxamides and Grignard reagents to formalkyl-substituted derivatives.

[0542] A 5 mL microwave reaction vessel was charged withbis(triphenylphosphine)palladium (II) chloride (0.030 mmol, 0.1 eq) andthe bromide (0.30 mmol). The vessel was evacuated and back-filled withargon gas. In a separate reaction vessel, solution of the Grignard (1.2mmol, 4 eq) was added to a 0.5 M solution of zinc chloride (1.2 mmol, 4eq) in tetahydrofuran at rt. The suspension was maintained for 30 minand the entire contents were transferred to the reaction vessel viacannula. The vessel was sealed and subjected to microwave irradiation at100° C. for 600 sec with a pre-stir time of 60 s. The reaction wasquenched with acetic acid (0.5 mL), diluted with methanol, and wastransferred to a SCX column. The column was washed with methanol (50 mL)and the product was eluted with 2 M ammonia in methanol (50 mL) andconcentrated. The residue was purified by chromatography [1/1 to 0/1ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)]followed by preparative HPLC using a 5/95 to 80/20 gradient ofacetonitrile (0.1% formic acid)/water (0.1% formic acid) over 6 min toprovide the product (20-50%). Alternatively, the residue was purified bychromatography (90/10/1 dichloromethane/methanol/ammonium hydroxide).

[0543] Procedure K

[0544] Procedure K provides a method for the preparation ofbromoindazoles from bromomethylanilines. (See, George V. DeLucca, U.S.Pat. No. 6,313,110.)

[0545] Acetic anhydride (2.27 eqiv) was added to a cooled (0° C.)solution of bromomethylaniline (1.00 eqiv) in chloroform (1.5 mL/mol)while maintaining the temperature below 40° C. The reaction mixture wasallowed to warm to room temperature and was maintained for 1 h.Potassium acetate (0.29 eq) and isoamyl nitrite (2.15 eqiv) was addedand the reaction mixture was heated at reflux for 18 h. The volatileswere removed under reduced pressure. Water (0.65 L/mol) was added to theresidue and the mixture was concentrated. Concentrated hydrochloric acid(1 L/mol) was added to the residue and the mixture was heated at 50° C.for 2 h. The mixture was allowed to cool to room temperature and the pHwas adjusted to 10 by the slow addition of a 50% aqueous sodiumhydroxide solution. The mixture was diluted with water (0.65 L/mol) andwas extracted with ethyl acetate (2×1.2 L/mol). The combined extractswere washed with brine (1 L/mol) and dried over anhydrous sodiumsulfate. The organic solution was filtered through a plug of silica gel(ethyl acetate wash), concentrated, and the residue was triturated withheptane (1 L/mol). The solids were collected by filtration, rinsed withheptane, and dried in a vacuum oven.

[0546] Procedure L

[0547] Procedure L provides a method for the preparation of indazolecarboxylic acid from bromoindazole.

[0548] To a solution of bromoindazole (1.00 eqiv) in anhydroustetrahydrofuran (7 L/mol) at room temperature was added sodium hydride(60% in mineral oil, 1.11 eqiv) in several portions. The resultingsolution was maintained for 30 min at room temperature and was thencooled to −60° C. A 1.3 M solution of sec-butyllithium in cyclohexane(2.1 eqiv) was added to the reaction mixture while maintaining theinternal temperature below −50° C. The mixture was maintained for anadditional 2 h at −50° C. A steady stream of anhydrous carbon dioxidewas bubbled through the reaction mixture for 1 h. The flow was continuedwhile the reaction mixture was allowed to warm to room temperature.Brine (6 L/mol) was added and the pH of the mixture was adjusted to 5with concentrated hydrochloric acid. The mixture was extracted with warmethyl acetate (3×8 L/mol) and the combined extracts were washed withsmall volume of brine, dried over anhydrous sodium sulfate, andconcentrated. The product was purified by chromatography on silica gelor by crystallization.

[0549] Procedure M

[0550] Procedure M provides a preparation of1H-indazole-7-carboxylicacid from 2-amino-3-methylbenzoic acid.

[0551] To a solution of 2-amino-3-methylbenzoic acid (10.1 g, 66.9 mmol)in NN-dimethylformamide (200 mL) was added cesium carbonate (33.2 g, 102mmol, 1.5 eq). The mixture was stirred for 30 min. A solution of methyliodide (4.17 mL, 67.0 mmol, 1.0 eq) in N,N-dimethylformamide (50 mL) wasadded dropwise and the reaction mixture was maintained for 18 h at rt.The reaction mixture was partitioned between water (1 L) and ether (200mL) and the water layer was extracted with an additional volume of ether(100 mL). The combined extracts were washed with brine (500 mL), driedover anhydrous potassium carbonate, and concentrated to provide 10.2 g(92%) of methyl 2-amino-3-methylbenzoate. ¹H NMR (400 MHz, CDCl₃) δ 7.77(d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82 (bs, 2H), 3.86 (s, 3H), 2.17(s, 3H).

[0552] To a solution of the ester (17.5 g, 106 mmol) in chloroform (300mL) was added acetic anhydride (22.6 mL, 239 mmol, 2.3 eq) whilemaintaining the temperature below 40° C. The reaction mixture wasmaintained at room temperature for 1 h when potassium acetate (3.00 g,30.6 mmol, 0.3 eq) and isoamyl nitrite (30.6 mL, 228 mmol, 2.2 eqiv) wasadded. The reaction mixture was heated at reflux for 24 h and wasallowed to cool to room temperature. The reaction mixture was washedwith a saturated, aqueous solution of sodium bicarbonate, dried oversodium sulfate, and concentrated. Methanol (100 mL) and 6 N hydrochloricacid (100 mL) were added to the residue and the mixture was maintainedfor 18 h at rt. The volatiles were removed under reduced pressure andthe residue was triturated with ethyl acetate (100 mL). The product wasisolated by filteration, washed with ethyl acetate (20 mL), and dried toprovide 15.3 g (68%) of methyl1H-indazole-7-carboxylate hydrochloride.¹H NMR (500 MHz, DMSO-d₆) δ 13.3 (bs, 1H), 8.26 (d, 1H), 8.12 (d, 1H),8.25 (dd, 1H), 7.27 (t, IH), 3.97 (s, 3H); MS (APCI) m/z 177 (M⁺+1).

[0553] A solution of the indazole (8.30 g, 33.0 mmol) in methanol (100mL) at 0° C. was treated with an 29% aqueous solution of potassiumhydroxide (20 mL). The reaction mixture was allowed to warm to rt andwas maintained for 18 h. The pH of the solution was adjusted to 5.5 bythe addition of concentrated hydrochloric acid and the volatiles wereremoved under reduced pressure. The residue was partitioned betweenbrine (100 mL) and ethyl acetate (200 mL) and the aqueous layer wasextracted with additional warm ethyl acetate (200 mL). The combinedorganic extracts were dried over anhydrous sodium sulfate andconcentrated. The residue was triturated with ethyl acetate (30 mL) andthe solids were isolated by filtration, thus providing 5.86 g (94%) ofthe acid.

[0554] Procedure N

[0555] Procedure N provides a preparation of substitutedbenzisothiazole-3-carboxylic acids from the corresponding thiophenols.

[0556] To a solution of 3-methoxythiophenol (3.75 g, 26.7 mmol) in ether(20 mL) was added oxalyl chloride (3.7 mL, 43 mmol) dropwise. Themixture was heated at reflux for 1.5 h, cooled to rt, and concentratedin vacuo. The resulting yellow oil was dissolved in dichloromethane (50mL), cooled to 0° C., and was treated with aluminum chloride (4.30 g,32.0 mmol) in portions. The mixture was heated at reflux for 30 min,cooled to rt, and poured onto ice water with stirring. The organic layerwas separated and successively washed with saturated, aqueous sodumbicarbonate, water, and brine. The organic layer was dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by chromatography (4/1 ethyl acetate/hexane) which provided2.46 g (47%) of 6-methoxy-1-benzothiophene-2,3-dione as an orange solid.

[0557] To a mixture of the dione (86 mg, 0.44 mmol) in 30% aqueoussolution of ammonium hydroxide (2.0 mL) was added 35% aqueous solutionhydrogen peroxide (0.2 mL) and the reaction mixture was maintained for12 h. The precipitated pink solids were isolated by filtration, washedwith water, and dried under high vacuum to afford 39 mg (42%) of6-methoxybenzisothiazole-3-carboxamide.

[0558] To a solution of the amide (1.14 g, 5.46 mmol) in methanol (100mL) was added 10 N sodium hydroxide (12 mL). The mixture was heated atreflux for 12 h, cooled to rt, and was acidified to pH <2 by the slowaddition of conc. hydrochloric acid. The organic layer was extractedwith dichloromethane (2×) and was dried over sodium sulfate. The crudeproduct was purified by chromatography (300/50/1dichloromethane/methanol/formic acid) to provide 1.02 g (89%) of6-methoxybenzisothiazole-3-carboxylic acid as a pink solid. LC/MS (EI)t_(R) 6.17 min, m/z 210 (M⁺+1).

[0559] The following acids were prepared by this method:

[0560] Benzisothiazole-3-carboxylic acid. ¹H NMR (CDCl₃) δ 8.86 (dd,J=7.1, 2.5, 1H), 8.03 (dd, J=6.3, 1.4, 1H), 7.66-7.61 (m, 2H); LC/MS(EI) t_(R) 6.75 min, m/z 180 (M⁺+1). 6-Bromobenzisothiazole-3-carboxylicacid. LC/MS (EI) t_(R) 9.95 min, m/z 258/260 (M⁺/M⁺+2).

[0561] 5-Methoxybenzisothiazole-3-carboxylic acid. LC/MS (EI) t_(R) 6.09min, m/z 210 (M⁺+1).

[0562] 5-Bromobenzisothiazole-3-carboxylic acid. LC/MS (EI) t_(R) 9.88min, m/z 258/260 (M⁺/M⁺+2).

[0563] 7-Methoxybenzisothiazole-3-carboxylic acid. LC/MS (EI) t_(R) 6.49min, m/z 210 (M⁺+1). 1511

[0564] Procedure O

[0565] Procedure O provides a method of preparation of1,3-benzothiazole-5-carboxylic acid from 4-chloro-3-nitrobenzoic acid.

[0566] To a solution of 4-chloro-3-nitrobenzoic acid (20.0 g, 99.2 mmol)in N,N-dimethylformamide (400 mL) was added potassium carbonate (35.0 g,254 mmol, 2.6 eqiv). After 30 min, ethyl iodide (18.6 g, 119 mmol, 1.2eqiv) was added and the reaction mixture was heated at 50° C. for 4 h.Water (3 L) was added and the mixture was extracted with diethyl ether(2×500 mL). The organic extracts were combined, washed with brine (1 L),dried over anhydrous sodium sulfate and concentrated on vacuum rotaryevaporator. The residue was crystallized from hexanes to provide 19.7 g(86%) of the ester. ¹H NMR (500 MHz, CDCl₃) δ 8.51 (d, 1H), 8.17 (dd,1H), 7.65 (d, 1H), 4.43 (q, 2H), 1.42 (t, 3H).

[0567] Sulfur (1.6 g, 49.91 mmol, 0.58 eqiv) was dissolved in a solutionof sodium sulfide nonahydrate (12.0 g, 49.96 mmol, 0.58 eqiv) in water(60 mL). This solution was combined with a solution of ethyl4-chloro-3-nitrobenzoate (19.6 g, 85.36 mmol, 1.00 eqiv) in ethanol (100mL) and the resulting mixture was heated at reflux for 3h. The hotreaction mixture was poured into water (600 mL) and maintained for 15min. The product was isolated by filteration and recrystallized fromethanol to provide 16.5 g (77%) of the disulfide. ¹H NMR (500 MHz,CDCl₃) δ 8.96 (d, 1H), 8.19 (dd, 1H), 7.88 (d, 1H), 4.43 (q, 2H), 1.41(t, 3H).

[0568] A mixture of diethyl 4,4′-dithiobis(3-nitrobenzoate) (11.2 g,24.8 mmol) and zinc granules (15.0 g, 234 mmol, 9.5 eq) in formic acid(600 mL) was heated to reflux for 48 h. The mixture was allowed to coolto room temperature and concentrated to dryness. The residue waspartitioned between ethyl acetate (500 mL) and saturated aqueous sodiumbicarbonate (500 mL). The organic layer was separated, dried overanhydrous sodium sulfate and concentrated. The residue waschromatographed on neutral Alumina ({fraction (1/1)} to {fraction (0/1)}hexanes/dichloromethane) to provide 5.30 g (51%) of the benzthiazole. ¹HNMR (500 MHz, CDCl₃) δ 9.08 (s, 1H), 8.83 (d, 1H), 8.14 (dd, 1H), 8.02(d, 1H), 4.45 (q, 2H), 1.44 (t, 3H); MS (EI) m/z 208 (M⁺+1).

[0569] To a solution of ethyl 1,3-benzothiazole-5-carboxylate (5.30 g,25.6 mmol) in a mixture of methanol (150 mL), tetrahydrofuran (40 mL)and water (5 mL) was added a 50% aqueous solution of sodium hydroxide(10 mL). The mixture was maintained at rt for 18 h and was concentrated.The residue was partitioned between water (300 mL) and diethyl ether(200 mL) and the organic layer was removed. Concentrated hydrochloricacid was added to the aqueous layer to adjust the pH to 4 and themixture was extracted with ethyl acetate (3×300 mL). The combinedextracts were washed with brine (200 mL), dried over anhydrous sodiumsulfate, and concentrated to yield 4.30 g (94%) the acid.

[0570] Procedure P

[0571] Procedure P provides a method for the preparation of1,3-benzothiazole-7-carboxylic acid from ethyl 3-aminobenzoate. (See,Kunz et. al. U.S. Pat. No. 5,770,758.)

[0572] A solution of ethyl 3-aminobenzoate (14.9 g, 90 mmol) inchlorobenzene (100 mL) was cooled to −10° C. and treated with sulfuricacid (97%, 2.5 mL, 45 mmol, 0.50 eq), dropwise. After 15 min, solidpotassium thiocyanate (9.2 g, 95 mmol, 1.05 eq) was added in severalportions over 30 min followed by 18-crown-6 (250 mg). The mixture washeated at 100° C. for 10 h, allowed to cool to rt, and was maintainedfor an additional 4 h. The precipitated solids were isolated byfiltration and were washed successively with chlorobenzene (25 mL) andhexanes (3×100 mL). The solid was suspended in water (300 mL) and thesuspension was maintained 30 min. The product was isolated by filtrationand washed with water (2×100 mL). The product was dried in a vacuum oven(55° C.) overnight to yield 13.4 g (69%) of the thiocarbamate. 1H NMR(500 MHz, DMSO-d₆) δ 1.32 (t, J=7.5, 3H), 4.32 (q, J=7, 2H), 7.44-7.47(m, 2H), 7.68-7.76 (m, 3H), 8.05 (s, 1H), 9.86 (s, 1H); MS (APCI) m/z225 (M⁺+1).

[0573] A solution of thiocarbamate (1.95 g, 12.2 mmol, 2.11 eqiv) inchloroform (10 mL) was added dropwise over a period of 40 min to avigorously maintained mixture of ethyl3-[(aminocarbonothioyl)amino]benzoate (1.30 g, 5.78 mmol, 1.00 eqiv),glacial acetic acid (10 mL) and chloroform (10 mL). The mixture wasmaintained 30 min at rt and then was heated at 70° C. for 4 h. Themixture was allowed to cool to room temperature and maintained for anadditional 13 h. The volatiles were removed under reduced pressure andthe solid residue was suspended in a mixture of chloroform (10 mL) andacetone (10 mL). The product was isolated by filtration, washedsuccessively with acetone (5 mL) and hexanes (10 mL), and dried in avacuum oven to provide 1.65 g (95%) of product as a mixture of ethyl2-amino-1,3-benzothiazole-7-carboxylate hydrobromide and ethyl2-amino-1,3-benzothiazole-5-carboxylate hydrobromide in a ratio of 95/5,respectively. This product was partitioned between saturated aqueoussolution of sodium bicarbonate (25 mL) and a mixture of ethyl acetate(70 mL) and tetrahydrofuran (30 mL). The organic layer was separated,dried over anhydrous sodium sulfate and concentrated. The residue wascrystallized form ethyl acetate to provide pure ethyl2-amino-1,3-benzothiazole-7-carboxylate. 1H NMR (500 MHz, DMSO-d₆) δ1.35 (t, J=7.5, 3H), 4.36 (q, J=7, 2H), 7.35 (t, J=7.5, 1H), 7.57 (d,J=7, 1H), 7.61 (bs, 2H), 7.65 (d, J=8, 1H); MS (EI) m/z 223 (M⁺+1).iso-Amylnitrite (7.4 mL, 53 mmol, 2.2 eqiv) was added to a solution ofethyl 2-amino-1,3-benzothiazole-7-carboxylate (5.40 g, 24.3 mmol) intetrahydrofuran (70 mL) and the mixture was heated at reflux for 4 h.The volatiles were removed under reduced pressure and the residue waspurified by chromatography (0/100 to 5/95 methanol/dichloromethane) toprovide 3.56 g (71%) of the ester. 1H NMR (500 MHz, CDCl₃) δ 1.47 (t,J=7.5, 3H), 4.49 (q, J=7, 2H), 7.62 (t, J=8, 1H), 8.20 (d, J=6.5, 1H),8.33 (d, J=8, 1H), 9.12 (s, 1H); MS (EI) m/z 208 (M⁺+1). Aqueous sodiumhydroxide (50%, 10 mL) was added to a 0{square root} C. solution ofethyl 1,3-benzothiazole-7-carboxylate (3.5 g, 16.89 mmol) in a mixtureof methanol (65 mL), tetrahydrofuran (20 mL) and water (5 mL). Themixture was maintained at room temperature for 4 h and the volatileswere removed under reduced pressure. The residue was dissolved in water(100 mL) and concentrated hydrochloric acid was added to adjust pH ofthe solution to 5. The mixture was cooled to 0° C. and maintained for 30min. The product was isolated by filtration, washed with water (10 mL),and dried in vacuum oven (70° C.) overnight to yield 2.75 g (91%) of theacid. 1H NMR (500 MHz, DMSO-d₆) δ 7.71 (t, J=7.5, 1H), 8.15 (d, J=7,1H), 8.38 (d, J=8, 1H), 9.51 (s, 1H), 13.74 (bs, 1H); MS (APCI) m/z 178(M⁺−1).

[0574] Procedure Q

[0575] Procedure Q provides a method for the conversion of brominatedisatins to the corresponding indazole-3-carboxylic acids.

[0576] The conversion of the substituted isatins to the correspondingindazole-3-carboxylic acids is essentially the same method as describedfor indazole-3-carboxylic acid: Snyder, H. R., et. al. J. Am. Chem. Soc.1952, 74, 2009. The substituted isatin (22.1 mmol) was diluted with 1 Nsodium hydroxide (24 mL) and was heated at 50° C. for 30 min. Theburgundy solution was allowed to cool to rt and was maintained for 1 h.The reaction mixture was cooled to 0° C. and was treated with a 0° C.solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solutionwas added through a pipet submerged below the surface of a vigorouslystirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0° C. Theaddition took 15 min and the reaction was maintained for an additional30 min. A cold (0 ° C.) solution of tin (II) chloride dihydrate (52.7mmol) in concentrated hydrochloric acid (20 mL) was added to thereaction mixture over 10 min and the reaction mixture was maintained for60 min. The precipitated solids were isolated by filtration, washed withwater, and dried to give a quantitative mass balance. This material wasof sufficient purity (1H NMR and LC/MS) to use in the next step withoutfurther purification.

[0577] Using the above Procedures and further procedures describedbelow, the following compounds in Examples 1-94 were prepared:

Example 1N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)benzoldlisothiazole-3-carboxamide

[0578]

[0579] Prepared from benzo[d]isothiazole-3-carboxylic acid usingProcedure B. Yield 42%. 1H NMR (CD₃OD) δ 8.73 (d, J=8.0, 1H), 8.05 (d,J=8.1, 1H), 7.59-7.47 (m, 2H), 4.19-4.16 (m, 1H), 3.37-3.28 (m, 1H),3.05-2.96 (m, 1H), 2.86-2.79 (m, 2H), 2.07-2.04 (m, 1H), 2.02-1.80 (m,1H), 1.78-1.74 (m, 1H), 1.56-1.52 (m, 1H); LC/MS (EI) t_(R) 3.61 min,m/z 288 (M⁺+1).

Example 2N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamidehydrochloride.

[0580]

[0581] Prepared from benzo[d]isothiazole-3-carboxylic acid usingProcedure C. Yield 95%. LC/MS (EI) t_(R) 3.55 min, m/z 288 (M⁺+1).

Example 3N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamide

[0582]

[0583] Prepared from benzo[d]isothiazole-3-carboxylic acid usingProcedure B. Yield 44%. LC/MS (EI) t_(R) 3.71 min, m/z 288 (M⁺+1).

Example 4N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamidehydrochloride

[0584]

[0585] Prepared from benzo[d]isothiazole-3-carboxylic acid usingProcedure C. Yield 95%. LC/MS (EI) t_(R) 3.71 min, m/z 288 (M⁺+1).

Example 5 N-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide

[0586]

[0587] Prepared from1H-indazole-3-carboxylic acid using Procedure A.Yield 50%. 1H NMR (CD₃OD) δ 8.21 (m, 1H), 7.56 (m, 1H), 7.42 (m, 1H),7.24 (m, 1H), 4.19 (m, 1H), 3.32 (m, 1H), 2.96 (m, 5H), 1.95 (m, SH); MS(EI) m/z 271(M⁺+1).

Example 6 N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamidehydrochloride

[0588]

[0589] Prepared from1H-indazole-3-carboxylic acid using Procedure C.Yield 76%. 1H NMR (400 MHz CD₃OD) δ 8.19 (d, J=8.4, 1H), 7.60 (d, J=8.4,1H), 7.43 (m, 1H), 7.26 (m, 1H), 4.55 (m, 1H), 3.85 (m, 1H), 3.50 (m,1H), 3.34 (m, 4H), 2.39 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.95 (m,1H); MS (APCI) m/z 271 (M⁺+1); m.p. 295° C. (dec.).

Example 7 N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamidehydrochloride

[0590]

[0591] Prepared from 1H-indazole-3-carboxylic acid using Procedure C.Yield 53%. 1H NMR (500 MHz, CD₃OD) δ 8.19 (d, J=8.0, 1H), 7.60 (d,J=8.5, 1H), 7.43 (m, 1H), 7.26 (m, 1H), 4.55 (m, 1H), 3.85 (m, 1H), 3.50(m, 1H), 3.34 (m, 4H), 2.39 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.95(m, 1H); MS (APCI) m/z 271 (M⁺+1); m.p. dec. 305° C.

Example 8N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzoldlisothiazole-3-carboxamide

[0592]

[0593] Prepared from 5-bromobenzo[d]isothiazole-3-carboxylic acid usingProcedure B. Yield 5%. LC/MS (EI) t_(R) 4.7 min, m/z 365 (M⁺+1).

Example 9N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(methoxy)benzoldlisothiazole-3-carboxamidehydroformate

[0594]

[0595] Prepared from 5-methoxybenzo[d]isothiazole-3-carboxylic acidusing Procedure B. Yield 5%. LC/MS (EI) t_(R) 3.14 min, m/z 318 (M⁺+1).

Example 10N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide

[0596] 5-Bromo-1H-indazole-3-carboxylic Acid.

[0597] Prepared from 5-bromoisatin using Procedure Q. 1H NMR (DMSO-d₆) δ13.9 (broad s, 1H), 8.23 (d, J=1.3, 1H), 7.67 (d, J=8.9, 1H), 7.57 (dd,J=8.9, 1.8, 1H).

[0598]N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide.

[0599] Prepared from 5-bromo-1H-indazole-3-carboxylic acid usingProcedure D. Yield 32%. 1H NMR (DMSO-d₆) δ 8.35 (d, J=7.2, 1H), 8.28 (d,J=1.4, 1H), 7.62 (d, J=8.8, 1H), 7.52 (dd, J=8.8, 1.8, 1H), 4.00 (m,1H), 3.11 (m, 2H), 2.90 (m, 1H), 2.67 (m, 4H), 1.82 (m,2H),1.59(t,J=5.6,2H), 1.30(m, 1H); 1HNMR(CD₃OD)δ 8.37(t,J=1.2, 1H), 7.53 (d,J=1.2, 2H), 4.22 (m, 1H), 3.33 (m, 1H), 3.02 (m, 1H), 2.84 (m, 4H), 2.06(m, 1H), 1.94 (m, 2H), 1.80 (m, 2H), 1.58 (m, 1H); MS (EI) m/z 349/351(M⁺/M⁺+2).

Example 11N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(cvclopropvl)-1H-indazole-3-carboxamidehydroformate

[0600]

[0601] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-1H-indazole-3-carboxamideusing Procedure J. Yield 20% 1H NMR (CD₃OD) δ 7.89 (s, 1H), 7.48 (d, J=8.7, 1H), 7.21 (dd, J=8.7, 1.6, 1H), 4.54 (m, 1H), 3.82 (m, 1H), 3.42(m, 1H), 3.35 (m, 4H), 2.38 (m, 1H), 2.28 (m, 1H), 2.11 (m, 3H), 1.92(m, 1H), 0.98 (m, 2H), 0.73 (m, 2H); MS (EI) m/z 311 (M⁺+1).

Example 12N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamidehydroformate

[0602]

[0603] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-1H-indazole-3-carboxamideusing Procedure H. Yield 3%. 1H NMR (CD₃OD) δ 8.47 (s, 1H), 7.93 (d, J=0.9, 1H), 7.68 (dd,J=8.8, 1.6, 1H), 7.59 (dd,J=8.9, 1.7, 2H), 6.87 (m,1H), 4.54 (m, 1H), 3.82 (m, 1H), 3.42 (m, 1H), 3.34 (m, 4H), 2.38 (m,1H), 2.27 (m, 1H), 2.11 (m, 2H), 1.93 (m, 1H); MS (EI) m/z 337 (M⁺+1).

Example 13N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamidehydroformate

[0604]

[0605] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-1H-indazole-3-carboxamideusing Procedure H. Yield 5%. 1H NMR (CD₃OD) δ 8.48 (s, 1H), 8.42 (s,1H), 7.74 (dd, J=8.7, 1.6, 1H), 7.67 (d, J=7.2, 2H), 7.46 (t, J=7.3,2H), 7.34 (t, J=7.4, 1H), 4.52 (m, 1H), 3.83 (m, 1H), 3.42 (m, 1H), 3.31(m, 4H), 2.39 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.92 (m, 1H); MS (EI)m/z 347 (M⁺+1).

Example 14N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3carboxamide

[0606]

[0607] Prepared from N-((3R)- 1 -azabicyclo[2.2.2]oct-3-yl)-5-bromo-1H-indazole-3-carboxamide using Procedure H. Yield 85%. 1HNMR (CD₃OD) δ 8.46 (t, J=0.8, 1H), 7.75 (dd, J=8.8, 1.7, 1H), 7.61 (dd,J=8.8, 0.7, 1H), 7.42 (dd, J=3.6, 1.1, 1H), 7.37 (dd, J=5.1, 1.0, 1H),7.11 (dd, J=5.1, 1.0, 1H), 7.10 (dd, J=5.1,3.6, 1H), 4.27 (m, 1H), 3.42(m, 1H), 3.12 (m, 1H), 2.93 (m, 4H), 2.11 (m, 1H), 1.93 (m, 1H), 1.84(m, 2H), 1.62 (m, 1H); MS (EI) m/z 353 (M⁺+1).

Example 15N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate

[0608]

[0609] Prepared from N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-1H-indazole-3-carboxamide using Procedure H.Yield 20%. 1HNMR (CD₃OD) δ 8.45 (t, J=0.8, 1H), 8.39 (broad s, 1H), 7.78 (dd, J=8.8,1.7, 1H), 7.62 (dd, J=8.8, 0.8, 1H), 7.42 (dd, J=3.6, 1.1, 1H), 7.38(dd, J=5.1, 1.0, 1H), 7.11 (dd, J=5.1, 3.6, 1H), 4.55 (m, 1H), 3.83 (m,1H), 3.46 (m, 1H), 3.37 (m, 4H), 2.40 (m, 1H), 2.25 (m, 1H), 2.10 (m,2H), 1.93 (m, 1H); MS (EI) m/z 353 (M⁺+1).

Example 16N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate

[0610]

[0611] Prepared from N-((3R)- 1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-1H-indazole-3-carboxamide usingProcedure H. Yield 5%. ¹H NMR (CD₃OD) δ 8.55 (broad s, 1H), 8.45 (d,J=0.7, 1H), 7.78 (dd, J=8.8, 1.6, 1H), 7.62 (m, 1H), 7.51 (m, 2H), 4.52(m, 1H), 3.78 (m, 1H), 3.42 (m, 1H), 3.35 (m, 4H), 2.37 (m, 1H), 2.25(m, 1H), 2.06 (m, 2H), 1.90 (m, 1H); MS (EI) m/z 353 (M⁺+1).

Example 17N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzoldiisothiazole-3-carboxamide

[0612]

[0613] Prepared from 5-bromobenzo[d]isothiazole-3-carboxylic acid usingProcedure B. Yield 5%. LC/MS (EI) t_(R) 5.36 min, m/z 365 (M⁺+1).

Example 18N-((3S)-1-Azabicyclo12.2.21oct-3-yl)-5-methoxybenzo[d]isothiazole-3-carboxamidehydroformate

[0614]

[0615] Prepared from 5-methoxybenzo[d]isothiazole-3-carboxylic acidusing Procedure B. Yield 7%. LC/MS (EI) t_(R) 3.38 min, m/z 318 (M⁺+1).

Example 19N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide

[0616]

[0617] Prepared from 5-bromo-1H-indazole-3-carboxylic acid usingProcedure D. Yield 31%. 1H NMR (DMSO-d₆) δ 8.35 (d, J=7.2, 1H), 8.28 (d,J=1.4, 1H), 7.62 (d, J=8.8, 1H), 7.52 (dd, J=8.8, 1.8, 1H), 4.00 (m,1H), 3.11 (m, 2H), 2.90 (m, 1H), 2.67 (m, 4H), 1.82 (m, 2H), 1.59 (t,J=5.6, 2H), 1.30 (m, 1H); 1H NMR (CD₃OD) δ 8.37 (t, J=1.2, 1H), 7.53 (d,J=1.2, 2H), 4.22 (m, 1H), 3.33 (m, 1H), 3.02 (m, 1H), 2.84 (m, 4H), 2.06(m, 1H), 1.94 (m, 2H), 1.80 (m, 2H), 1.58 (m, 1H); MS (EI) m/z 349/351(M⁺/M⁺+2). Example 20

N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamiidehydroformate

[0618]

[0619] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-1H-indazole-3-carboxamideusing Procedure H. Yield 11%. 1H NMR (CD₃OD) δ 8.47 (s, 1H), 7.93 (d,J=0.9, 1H), 7.68 (dd, J=8.8, 1.6, 1H), 7.59 (dd, J=8.9, 1.7, 2H), 6.87(m, 1H), 4.54 (m, 1H), 3.82 (m, 1H), 3.42 (m, 1H), 3.34 (m, 4H), 2.38(m, 1H), 2.27 (m, 1H), 2.11 (m, 2H), 1.93 (m, 1H); MS (EI) m/z 337(M⁺+1).

Example 21N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamidehydroformate

[0620]

[0621] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-1H-indazole-3-carboxamideusing Procedure H. Yield 12%. 1H NMR (CD₃OD) δ 8.48 (s, 1H), 8.42 (s,1H), 7.74 (dd, J=8.7, 1.6, 1H), 7.67 (d, J=7.2, 2H), 7.46 (t, J=7.3,2H), 7.34 (t, J=7.4, 1H), 4.52 (m, 1H), 3.83 (m, 1H), 3.42 (m, 1H), 3.31(m, 4H), 2.39 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.92 (m, 1H); MS (EI)m/z 347 (M⁺+1).

Example 22N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate.

[0622]

[0623] Prepared from N-((3S)- 1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-1H-indazole-3-carboxamide usingProcedure H.Yield 45%. ¹H NMR (CD₃OD) δ 8.45 (t, J=0.8, 1H), 8.39 (broads, 1H), 7.78 (dd, J=8.8, 1.7, 1H), 7.62 (dd, J=8.8, 0.8, 1H), 7.42 (dd,J=3.6, 1.1, 1H), 7.38 (dd, J=5.1, 1.0, 1H), 7.11 (dd, J=5.1, 3.6, 1H),4.55 (m, 1H), 3.83 (m, 1H), 3.46 (m, 1H), 3.37 (m, 4H), 2.40 (m, 1H),2.25 (m, 1H), 2.10 (m, 2H), 1.93 (m, 1H); MS (EI) m/z 353 (M⁺+1).

Example 23N-((3S)-1-Azabicyclo[12.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate

[0624]

[0625] Prepared from N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-1H-indazole-3 -carboxamide using Procedure H. Yield 20%. 1HNMR (CD₃OD) δ 8.55 (broad s, 1H), 8.45 (d, J=0.7, 1H), 7.78 (dd,J=8.8,1.6, 1H), 7.62 (m, 1H), 7.51 (m, 2H), 4.52 (m, 1H), 3.78 (m, 1H),3.42 (m, 1H), 3.35 (m, 4H), 2.37 (m, 1H), 2.25 (m, 1H), 2.06 (m, 2H),1.90 (m, 1H); MS (EI) m/z 353 (M⁺+1).

Example 24N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-bromobenzoldlisothiazole-3-carboxamide.

[0626]

[0627] Prepared from 6-bromobenzo[d]isothiazole-3-carboxylic acid usingProcedure B. Yield 39%. LC/MS (EI) t_(R) 4.75 min, m/z 365 (M⁺+1).

Example 25 N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-cyclopropylbenzoIdlisothiazole-3-carboxamide

[0628]

[0629] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure J. Yield 45%. LC/MS (EI) t_(R) 4.25 min, m/z 328 (M⁺+1).

Example 26N-((3R)-1-Azabicylo[2.2.2]oct-3-yl)-6-(2fluorophenyl)benzoldlisothiazole-3-carboxamide

[0630]

[0631] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 37%. LC/MS (EI) t_(R) 5.95 min, m/z 382 (M⁺+1).

Example 27N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(2fluorophenyl)benzoldlisothiazole-3-carboxamidehydroformate

[0632]

[0633] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 8%. LC/MS (EI) t_(R) 4.52 min, m/z 382(M⁺+1).

Example 28N-((3R)-1-Azabicylo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzoldlisothiazole-3-carboxamide

[0634]

[0635] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 38%. LC/MS (EI) t_(R) 5.92 min, m/z 382 (M⁺+1).

Example 29N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate

[0636]

[0637] Prepared from N-((3R)- 1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 10%. LC/MS (EI) t_(R) 4.56 min, m/z 382(M⁺+1).

Example 30N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamide

[0638]

[0639] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 34%. LC/MS (EI) t_(R) 5.92 min, m/z 382 (M⁺+1).

Example 31N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]iisothiazole-3-carboxamidehydroformate

[0640]

[0641] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 9%. LC/MS (EI) t_(R) 4.57 min, m/z 382 (M⁺+1).

Example 32N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-furan-3-yl)benzo[d]isothiazole-3-carboxamide

[0642]

[0643] Prepared from N-((3R)- 1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 14%. LC/MS (EI) t_(R) 4.32 min, m/z 354 (M⁺+1).

Example 33N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-furan-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate

[0644]

[0645] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 11%. LC/MS (EI) t_(R) 4.32 min, m/z 354 (M⁺+1).

Example 34N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxybenzo[d]isothiazole-3-carboxamide

[0646]

[0647] Prepared from 5-methoxybenzo[d]isothiazole-3-carboxylic acidusing Procedure B. Yield 73%. 1H NMR (CD₃OD) δ 8.59 (d, J=9.1, 1H), 7.59(d, J=2.2, 1H), 7.14 (dd, J =9.1, 2.3, 1H), 4.20 (m, 1H), 3.93 (s, 3H),3.37-3.28 (m, 1H), 3.05-2.96 (m, 1H), 2.86-2.79 (m, 2H), 2.07-2.04 (m,1H), 2.02-1.80 (m, 1H), 1.78-1.74 (m, 1H), 1.56-1.52 (m, 1H); LC/MS (EI)t_(R) 4.92 min, m/z 318m/z (M⁺+1).

Example 35N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(morpholin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate

[0648]

[0649] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure 1. Yield 34%. 1H NMR (CD₃OD) δ 8.54 (d, J=9.2, 1H), 7.45(d, J=2.1, 1H), 7.29 (dd, J=9.2, 2.2, 1H), 4.22-4.19 (m, 1H), 3.88-3.85(m, 2H), 3.68-3.65 (m, 2H), 3.38-3.30 (m, 5H), 3.09-3.01 (m, 2H),2.95-2.81 (m, 4H), 2.09-2.06 (m, 1H), 1.97-1.84 (m, 1H), 1.82-1.79 (m,2H), 1.62-1.54 (m, 1H); LC/MS (EI) t_(R) 4.77 min, m/z 373 (M⁺+1).

Example 36N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamide

[0650]

[0651] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 37%. LCIMS (EI) t_(R) 5.99 min, m/z 364 (M⁺+1).

Example 37N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamidehydroformate

[0652]

[0653] Prepared from N-((3R)- 1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 3%. LC/MS (EI) t_(R) 5.99 min, m/z 364 (M⁺+1).

Example 38N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pvridin-3-yl)benzo[d]isothiazole-3-carboxamide

[0654]

[0655] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 19%. LC/MS (EI) t_(R) 2.94 min, m/z 365 (M⁺+1).

Example 39N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate

[0656]

[0657] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-y1)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 5%. LC/MS (EI) t_(R) 2.94 min, m/z 365 (M⁺+1).

Example 40N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamide

[0658]

[0659] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 15%. LC/MS (EI) t_(R) 2.96 min, m/z 365 (M⁺+1).

Example 41N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate

[0660]

[0661] Prepared from N-((3R)- 1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 2%. LC/MS (EI) t_(R) 1.56 min, m/z 365 (M⁺+1).

Example 42N-((3R)-1-Azabicylo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)benzo[d]isothiazole-3-carboxamide

[0662]

[0663] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 16%. LC/MS (EI) t_(R) 4.52 min, m/z 370 (M⁺+1).

Example 43N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)benzo[d]isothiazole-3-carboxamide

[0664]

[0665] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 61%. 1H NMR (CD₃OD) δ 8.74 (d, J=8.6, 1H), 8.36(s, 1H), 7.85 (dd, J=8.6, 1.4, 1H), 7.62 (d, J=3.5, 1H), 7.51 (m, 1H),7.17 (dd, J=5.0, 3.7, 1H), 4.52 (M, 1H), 3.87-3.79 (m, 1H), 3.75-3.70(m, 1H), 3.47-3.19 (m, 4H), 2.40 (m, 1H), 2.26 (m, 1H), 2.11 (m, 1H),1.93 (m, 1H); LC/MS (EI) t_(R) 4.42 min, m/z 370 (M⁺+1).

Example 44N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(bromo)-1H-indazole-3-carboxamide

[0666] 6-Bromo-1H-indazole-3-carboxylic acid

[0667] Prepared from 6-bromoisatin using Procedure Q. 1H NMR (DMSO-d₆) δ13.7 (broad s, 1H), 8.02 (d,J=8.5, 1H), 7.60 (d,J=1.3, 1H), 7.43(dd,J=8.7, 1.3, 1H).

N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(bromo)-1H-indazole-3-carboxamide

[0668]

[0669] Prepared from 6-bromo-1H-indazole-3-carboxylic acid usingProcedure D. Yield 23%. 1HNMR (CD₃OD) δ 8.10 (d, J=8.7, 1H), 7.78 (s,1H), 7.37 (d, J=8.7, 1H), 4.20 (m, 1H), 3.30 (m, 6H), 2.08 (m, 1H), 1.95(m, 1H), 1.83 (m, 2H), 1.80 (m, 1H); MS (EI) m/z 349/351 (M⁺/M⁺+2).

Example 45N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)-1H-indazole-3-carboxamidehydroformate

[0670]

[0671] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-1H-indazole-3-carboxamideusing Procedure H. Yield 12%. 1H NMR (CD₃OD) δ 8.49 (s, 1H), 8.16 (m,1H), 8.00 (s, 1H), 7.71 (m, 1H), 7.59 (m, 1H), 7.52 (m, 1H), 7.50 (m,1H), 4.53 (m, 1H), 3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H), 2.30 (m,1H), 2.10 (m, 2H), 1.85 (m, 1H); MS (EI) m/z 337 (M⁺+1).

Example 46N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamidehydroformate

[0672]

[0673] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-1H-indazole-3-carboxamideusing Procedure H. Yield 12%. 1H NMR (CD₃OD) δ 8.39 (s, 1H), 8.24 (m,1H), 7.77 (s, 1H), 7.68 (m, 2H), 7.57 (m, 1H), 7.50 (m, 2H), 4.53 (m,1H), 3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H), 2.30 (m, 1H), 2.10 (m,2H), 1.85 (m, 1H); MS (EI) m/z 347 (M⁺+1).

Example 47N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate

[0674]

[0675] Prepared fromN-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-1H-indazole-3-carboxamideusing Procedure H. Yield 13%. 1H NMR (CD₃OD) δ 8.49 (s, 1H), 8.21 (m,1H), 7.81 (s, 1H), 7.74 (m, 1H), 7.64 (m, 1H), 7.53 (m, 2H), 4.53 (m,1H), 3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H), 2.30 (m, 1H), 2.10 (m,2H), 1.85 (m, 1H); MS (EI) m/z 353 (M⁺1).

Example 48N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate

[0676]

[0677] Prepared from N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-1H-indazole-3-carboxamide using Procedure H.Yield 19%. 1H NMR (CD₃OD) δ 8.48 (s, 1H), 8.20 (m, 1H), 7.80 (s, 1H),7.62 (m, 1H), 7.51 (m, 1H), 7.44 (m, 1H), 7.13 (m, 1H), 4.53 (m, 1H),3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H), 2.30 (m, 1H), 2.10 (m, 2H),1.85 (m, 1H); MS (EI) m/z 353 (M⁺+1).

Example 49N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamide

[0678]

[0679] Prepared from 6-bromobenzo[d]isothiazole-3-carboxylic acid usingProcedure B. Yield 33%. LC/MS (EI) t_(R) 5.44 min, m/z 365 (M⁺+1).

Example 50N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-cvclopropylbenzo[d]isothiazole-3-carboxamide

[0680]

[0681] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure J. Yield 40%. LC/MS (EI) t_(R) 4.23 min, m/z 328(M⁺+1).

Example 51N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate

[0682]

[0683] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 13%. LC/MS (EI) t_(R) 4.52 min, m/z 382 (M⁺+1).

Example 52N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate

[0684]

[0685] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 8%. LC/MS (EI) t_(R) 4.56 min, m/z 382 (M⁺+1).

Example 53N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate

[0686]

[0687] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 15%. LC/MS (EI) t_(R) 4.56 min, m/z 382 (M⁺+1).

Example 54N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate

[0688]

[0689] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 24%. LC/MS (EI) t_(R) 4.29 min, m/z 354 (M⁺+1).

Example 55N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxybenzo[d]isothiazole-3-carboxamide

[0690]

[0691] Prepared from 5-methoxybenzo[d]isothiazole-3-carboxylic acidusing Procedure B. Yield 73%. LC/MS (EI) t_(R) 4.93 min, m/z 318 (M⁺+1).

Example 56N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(morpholin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate

[0692]

[0693] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure I. Yield 5%. LC/MS (EI) t_(R) 2.93 min, m/z 373 (M⁺+1).

Example 57N-((3S)-1-Azabicyclol[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamidehydroformate

[0694]

[0695] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 9%. LC/MS (EI) t_(R) 4.53 min, m/z 364 (M⁺+1).

Example 58N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate

[0696]

[0697] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 8%. LC/MS (EI) t_(R) 2.72 min, m/z 365 (M⁺+1).

Example 59N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate

[0698]

[0699] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 5%. LC/MS (EI) t_(R) 2.63 min, m/z 365 (M⁺+1).

Example 60N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)benzo[d]isothiazole-3-carboxamidehydroformate

[0700]

[0701] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 27%. LC/MS (EI) t_(R) 4.48 min, m/z 370 (M⁺+1).

Example 61N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)benzo[d]isothiazole-3-carboxamide

[0702]

[0703] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamideusing Procedure H. Yield 61%. LC/MS (EI) t_(R) 4.41 min, m/z 370 (M⁺+1).

Example 62N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(bromo)-1H-indazole-3-carboxamide

[0704]

[0705] Prepared from 6-bromo-1H-indazole-3-carboxylic acid usingProcedure D. Yield 19%. 1H NMR (CD₃OD) δ 8.10 (d, J=8.7, 1H), 7.78 (s,1H), 7.37 (d, J=8.7, 1H), 4.20 (m, 1H), 3.30 (m, 6H), 2.08 (m, 1H), 1.95(m, 1H), 1.83 (m, 2H), 1.80 (m, 1H); MS (EI) m/z 349/351 (M⁺/M⁺+2).

Example 63N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)-1H-indazole-3-carboxamidehydroformate

[0706]

[0707] Prepared from N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-1H-indazole-3-carboxamide using Procedure H. Yield 12%. 1HNMR (CD₃OD) δ 8.49 (s, 1H), 8.21 (m, 1H), 7.81 (s, 1H), 7.74 (m, 1H),7.64 (m, 1H), 7.53 (m, 2H), 4.53 (m, 1H), 3.35 (m, 1H), 3.28 (m, 5H),2.37 (m, 1H), 2.30 (m, 1H), 2.10 (m, 2H), 1.85 (m, 1H); MS (EI) m/z 337(M⁺+1).

Example 64N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamidehydroformate

[0708]

[0709] Prepared fromN-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-1H-indazole-3-carboxamideusing Procedure H. Yield 13%. 1H NMR (CD₃OD) δ 8.49 (s, 1H), 8.25 (m,1H), 7.77 (s, 1H), 7.73 (m, 2H), 7.64 (m, 1H), 7.53 (m, 2H), 4.53 (m,1H), 3.35 (m, 1H), 3.28 (m, 5H), 2.37 (m, 1H), 2.30 (m, 1H), 2.10 (m,2H), 1.85 (m, 1H); MS (EI) m/z 347 (M⁺+1).

Example 65N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate

[0710]

[0711] Prepared from N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-1H-indazole-3-carboxamide using Procedure H. Yield 22%. 1HNMR (CD₃OD) δ 8.49 (s, 1H), 8.21 (m, 1H), 7.81 (s, 1H), 7.74 (m, 1H),7.64 (m, 1H), 7.53 (m, 2H), 4.53 (m, 1H), 3.35 (m, 1H), 3.28 (m, 5H),2.37 (m, 1H), 2.30 (m, 1H), 2.10 (m, 2H), 1.85 (m, 1H); MS (EI) m/z 353(M⁺+1).

Example 66N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate

[0712]

[0713] Prepared from N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-6-bromo-1H-indazole-3 -carboxamide using Procedure H. Yield 17%. 1HNMR (CD₃OD) δ 8.49 (s, 1H), 8.21 (m, 1H), 7.81 (s, 1H), 7.74 (m, 1H),7.64 (m, 1H), 7.53 (m, 2H), 4.53 (m, 1H), 3.35 (m, 1H), 3.28 (m, 5H),2.37 (m, 1H), 2.30 (m, 1H), 2.10 (m,2H), 1.85 (m, 1H); MS (EI) m/z 353(M⁺+1).

Example 67N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-7-methoxvbenzo[d]isothiazole-3-carboxamide

[0714]

[0715] Prepared from 7-methoxybenzo[d]isothiazole-3-carboxylic acidusing Procedure B. Yield 7%. LC/MS (EI) t_(R) 4.00 min, m/z 318 (M⁺+1).

Example 68N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-7-methoxybenzo[d]isothiazole-3-carboxamide

[0716]

[0717] Prepared from 7-methoxybenzo[d]isothiazole-3-carboxylic acidusing Procedure B. Yield 4%. LC/MS (EI) t_(R) 3.76 min, m/z 318 (M⁺+1).

Example 69N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)-N-(1H-indazol-3-ylmethyl)amine

[0718]

[0719] Prepared from 3-[(3R)-1 -azabicyclo[2,2,]oct-3-yl]-1H-indazole-3-carboxyamide using Procedure F. Yield 50%. 1H NMR (CD₃OD)δ 7.85 (m, 1H), 7.48 (d, J=8.4, 1H), 7.37 (dd, J=7.2, 8.4, 1H), 7.14(dd, J=7.2, 8.4, 1H), 4.12 (m, 2H), 3.02 (m, 1H), 2.88 (m, 5H), 2.50 (m,1H), 1.95 (m, 5H); MS (EI) m/z 257(M⁺+1).

Example 70 N-((3S)-1-Azabicyclo[2,2,2]oct-3-yl)-N-(1H-indazol-3-ylmethyl)amine

[0720]

[0721] Prepared from3-[(3S)-1-azabicyclo[2,2,]oct-3-yl]-1H-indazole-3-carboxyamide usingProcedure F. Yield 50%. 1H NMR (CD₃OD) δ 7.85 (m, 1H), 7.56 (m, 1H),7.37 (m, 1H), 7.11 (m, 1H),4.12 (m, 2H), 3.02 (m, 1H), 2.88 (m, 5H),2.50 (m, 1H), 1.95 (m, SH); MS (EI) m/z 257(M⁺+1).

Example 71N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-4-carboxamide

[0722] 4-Bromo-1H-indazole

[0723] Prepared from 3-bromo-2-methylaniline using Procedure K. Yield95%. 1H NMR (500 MHz, CDCl₃) δ 10.55 (bs, 1H); 8.12 (d, 1H), 7.46 (d,1H), 7.34 (d, 1H), 7.25 (dd, 1H).

[0724] 1H-Indazole-4-carboxylic acid

[0725] Prepared from 4-bromo-1H-indazole using Procedure L. Yield 55%.1H NMR (500 MHz, DMSO-d₆) δ 13.27 (bs, 2H), 7.85 (d, 1H), 7.84 (d, 1H),7.49 (t, 1H); MS (EI) m/z 161 (M⁺−1).

[0726] N-((3R)-1-Azabicyclo[2,2,21]oct-3-yl)-1H-indazole-4-carboxamide

[0727] Prepared from1H-indazole-4-carboxylic acid using Procedure A.Yield 50%. ¹H NMR (CD₃OD) δ 8.38 (d, J=0.9, 1H), 7.74 (d, J=8.4, 1H),7.62 (d, J=6.9, 1H), 7.46 (dd, J=6.9, 8.4, 1H), 4.39 (m, 1H), 3.62 (m,1H), 3.12 (m, 5H), 1.95 (m, 5H); MS (EI) m/z 271(M⁺+1).

Example 72 N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-4-carboxamide

[0728]

[0729] Prepared from 1H-indazole-4-carboxylic acid using Procedure A.Yield 50%. 1H NMR (CD₃OD) δ 8.40 (d, J=0.6, 1H), 7.75 (d, J=8.4, 1 H),7.67 (d, J=6.6, 1H), 7.45 (dd, J=6.6, 8.4, 1H), 4.49 (m, 1H), 3.77 (m,1H), 3.30 (m, 5H), 1.95 (m, 5H); MS (EI) m/z 271(M⁺+1).

Example 73 N-(1H-Indazol-4-yl)-1-azabicyclo[2,2,2]oct-3-ylcarboxamide

[0730]

[0731] Prepared from indazole-4-ylamine using Procedure E. Yield 30%. 1HNMR (CD₃OD₃) δ 8.20 (s, 1H), 7.55 (m, 1H), 7.36 (m, 2H), 3.92 (m, 1H),3.46 (m, SH), 2.56 (m, 1H), 2.06 (m, SH); MS (EI) m/z 271 (M⁺+1).

Example 74N-(l-Azabicyclo[2.2.2]oct-3-yl)-N-(1H-indazol-4-ylmethyl)amine

[0732]

[0733] Prepared from indazol-4-carboxaldehyde using Procedure G. Yield50%. 1H NMR (CD₃OD) δ 8.27 (s, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 7.17 (m,1H), 4.18 (m, 2H), 3.52 (m, 1H), 3.30 (m, 5H), 3.00 (m, 1H), 1.95 (m,5H); MS (EI) m/z 257 (M⁺+1).

Example 75N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-5-carboxamidehydrochloride

[0734] 1,3-Benzothiazole-5-carboxylic acid.

[0735] Prepared from 4-chloro-3-nitrobenzoic acid using Procedure O,Yield 4.30 g (94%) of pure product. 1H NMR (500 MHz, DMSO-d₆) δ 13.2(bs, 1H), 9.52 (s, 1H), 8.60 (d, 1H), 8.30 (d, 1H), 8.05 (dd, 1H); MS(ACPI) m/z 178 (M⁺−1).

[0736] N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-5-carboxamidehydrochloride.

[0737] Prepared from 1,3-benzothiazole-5-carboxalic acid using ProcedureC. Yield 92%. ¹H NMR (500 MHz, CD₃OD) δ 9.89 (s, 1H), 8.68 (s, 1H), 8.30(d, J=8.5, 1H), 8.14 (d, J=8.5, 1H), 4.53 (m, 1H), 3.87 (m, 1H), 3.58(m, 1H), 3.43 (m, 4H), 2.42 (m, 1H), 2.34 (m, 1H), 2.13 (m, 2H), 1.97(m, 1H); MS (APCI) m/z 288 (M⁺+1); m.p. 170-180° C.

Example 76N-((3S)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-5-carboxamidehydrochloride

[0738]

[0739] Prepared from 1,3-benzothiazole-5-carboxalic acid using ProcedureC. Yield 96%. ¹H NMR (500 MHz, CD₃OD) δ 9.77 (s, 1H), 8.66 (s, 1H), 8.27(d, J=8.5, 1H), 8.12 (d, J=8.5, 1H), 4.53 (m, 1H), 3.87 (m, 1H), 3.56(m, 1H), 3.40 (m, 4H), 2.42 (m, 1H), 2.33 (m, 1H), 2.13 (m, 2H), 1.97(m, 1H); MS (APCI) m/z 288 (M⁺+1); m.p. 166-176° C.

Example 77N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-5-carboxamide

[0740] 5-Bromo-1H-indazole

[0741] Prepared from 4-bromo-2-methylaniline using Procedure K. Yield88%. 1H NMR (500 MHz, CDCl₃) δ 10.4 (bs, 1H), 8.04 (s, 1H), 7.92 (s,1H), 7.47 (dd, J=1.0, 1H), 7.39 (d, J =8.5, 1H); MS (EI) m/z 197, 199(M⁺+1).

[0742] 1H-Indazole-5-carboxylic acid

[0743] Prepared from 5-bromo-1H-indazole using Procedure L. Yield 54%.1H NMR (500 MHz, DMSO-d₆) δ 3.18 (bs, 2H), 8.50 (t, 1H), 8.27 (d, 1H),7.95 (dd, 1H), 7.63 (dt, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ 167.71,141.64, 135.20, 126.61, 123.79, 123.12, 122.60, 110.04; MS (APCI) m/z161 (M⁺−1)

[0744] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-5-carboxamide.

[0745] Prepared from1H-indazole-5-carboxylic acid using Procedure A.Yield 50%. 1H NMR (CD₃OD) δ 8.34 (s, 1H), 8.15 (s, 1H), 7.88 (d, J=8.7,1H), 7.59 (d, J=8.7, 1H), 4.23 (m, 1H), 3.43 (m, 1H), 2.97 (m, 5H), 1.92(m, 5H); MS (EI) m/z 271(M⁺+1).

Example 78N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-5-carboxamide

[0746]

[0747] Prepared from 1H-indazole-5-carboxylic acid using Procedure A.Yield 50%. ¹H NMR (CD₃OD) δ 8.34 (s, 1H), 8.16 (s, 1H), 7.90 (d, J=9.0,1H), 7.60 (d, J=9.0, 1H), 4.30 (m, 1H), 3.54 (m, 1H), 3.05 (m, 5H), 1.92(m, 5H); MS (EI) m/z 271(M⁺+1).

Example 79 N-(1H-Indazol-5-yl)-1-azabicyclo[2.2.2]oct-3-ylcarboxamide

[0748]

[0749] Prepared from 1H-indazol-5-ylamine using Procedure E. Yield 30%.1H NMR (CD₃OD) δ 8.04 (m, 2H), 7.45 (m, 2H), 3.40 (m, 1H), 2.90 (m, 5H),2.16 (m, 1H), 1.90 (m, 5H); MS (EI) m/z 271 (M⁺+1).

Example 80 N-(1-Azabicyclo[2,22] oct-3-yl)benzothiazole-6-carboxamide

[0750]

[0751] Prepared from benzothiazole-6-carboxylic acid using Procedure A.Yield 60%. 1H NMR (CDCl₃) δ 9.14 (s, 1H), 8.50 (m, 1H), 8.20 (m, I1H),7.90 (m, 1H), 6.47 (m, 1H, NH), 4.25 (m, 1H), 3.45 (m, 2H), 2.78 (m,4H), 1.90 (m, 5H); MS (EI) m/z 288 (M⁺+1).

Example 82N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-6-carboxamidehydrochloride

[0752]

[0753] Prepared from 1,3-benzothiazole-6-carboxylic acid using ProcedureC. Yield 85%. 1H NMR (500 MHz, CD₃OD) δ 9.71 (s, 1H), 8.74 (t, J=1.0,1H), 8.16 (m, 2H), 4.51 (m, 1H), 3.85 (m, 1H), 3.53 (m, 1H), 3.37 (m,6H), 2.39 (m, 1H), 2.30 (m, 1H), 2.11 (m, 2H), 1.95 (m, 1H); MS (APCI)m/z 288 (M⁺+1); m.p. 285° C. (dec.).

Example 82N-((3S)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-6-carboxamidehydrochloride

[0754]

[0755] Prepared from 1,3-benzothiazole-6-carboxylic acid using ProcedureC. Yield 100%. ¹H NMR (500 MHz, CD₃OD) δ 9.75 (s, 1H), 8.75 (t, J=1.0,1H), 8.17 (m, 2H), 4.50 (m, 1H), 3.85 (m, 1H), 3.51 (m, 1H), 3.37 (m,7H), 2.40 (m, 1H), 2.31 (m, 1H), 2.11 (m, 2H), 1.95 (m, 1H); MS (APCI)m/z 288 (M⁺+1); m.p. dec. 287° C.

Example 83N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-2-(pyrrol-1-yl)benzothiazole-6-carboxamidehydroformate

[0756]

[0757] Prepared from 2-(pyrrol-1-yl)1,3-benzothiazole-6-carboxylic acidusing Procedure A. Yield 75%. 1H NMR (CD₃OD) δ 8.45 (s, 1H), 7.99 (d,J=8.4, 1H), 7.90 (d, J=8.4, 1H), 7.56 (d, J=2.1, 1H), 6.44 (d, J=2.1,1H), 4.47 (m, 1H), 3.87 (m, 1H), 3.40 (m, 4H), 2.39 (m, 1H), 2.28 (m,1H), 2.11 (m, 2H), 1.96 (m, 1H); MS (EI) m/z 353 (M⁺+1).

Example 84 N-(Benzothiazol-6-yl)-1-azabicyclo[2,2,2]oct-3-ylcarboxamide

[0758]

[0759] Prepared from benzothiazole-6-yl amine using Procedure E. Yield30%. 1H NMR (CD₃OD₃) δ 9.11 (s, 1H), 8.51 (s, 1H), 7.95 (d, J=9.0, 1H),7.62 (d, J=9.0, 1H), 3.44 (m, 1H), 2.88 (m, 6H), 2.13 (m, 1H), 1.74 (m,3H), 1.46 (m, 1H); MS (EI) m/z 288 (M⁺+1).

Example 85N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-6-carboxamide.

[0760] 6-Bromo-1H-indazole

[0761] Prepared from 5-bromo-2-methylaniline using Procedure K. Yield88%. 1H NMR (400 MHz, CDCl₃) δ 13.20 (bs, 1H), 8.10 (d, 1H), 7.76 (m,1H), 7.72 (dd, 1H), 7.24 (dd, 1H).

[0762] 1H-Indazole-6-carboxylic acid

[0763] Prepared from 6-bromo-1H-indazole using Procedure L. Yield 46%.1H NMR (500 MHz, DMSO-d₆) δ 13.24 (bs, 2H), 8.20 (d, 1H), 8.19 (m, 1H),7.87 (dd, 1H), 7.70 (dd, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ 167.53,139.32, 133.43, 128.23, 125.08, 120.47, 120.45, 112.10; MS (APCI) m/z161 (M+-1).

[0764] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-6-carboxamide.

[0765] Prepared from 1H-indazole-6-carboxylic acid using Procedure A.Yield 50%. 1H NMR (CD₃OD) δ 8.11 (s, 1H), 8.06 (s, 1H), 7.83 (d, J=8.4,1H), 7.60 (d, J=8.4, 1H), 4.24 (m, 1H), 3.35 (m, 1H), 2.97 (m, SH), 1.92(m, 5H); MS (EI) m/z 271(M⁺+1).

Example 86N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-6-carboxamide

[0766]

[0767] Prepared from 1H-indazole-6-carboxylic acid using Procedure A.Yield 50%. 1H NMR (CD₃OD) δ 8.11 (s, 1H), 8.06 (s, 1H), 7.84 (d, J=7.8,1H), 7.60 (d, J=7.8, 1H), 4.22 (m, 1H), 3.41 (m, 1H), 2.96 (m, 5H), 1.92(m, 5H); MS (EI) m/z 271(M⁺+1).

Example 87N-((3R)-1-Azabicyclol[2.2.2]oct-3-yl)-3-(thiophen-3-yl)-1H-indazole-6-carboxamidehydroformate

[0768]

[0769] Prepared from N-((3R)-1-azabicyclo[2.2 .2]oct-3-yl)-3-(iodo)-1H-indazole-6-carboxamide using Procedure H. Yield 28%.LC/MS (EI) t_(R) 4.17 min, m/z 353 (M⁺+1).

Example 88 N-(1H-Indazol-6-yl)-1-azabicyclo[2,2,2]oct-3-ylcarboxamide

[0770]

[0771] Prepared from indazole-6-yl amine using Procedure E. Yield 30%.1H NMR (CD₃OD₃) δ 8.18 (s, 1H), 7.92 (s, 1H), 7.62 (m,1H), 7.62 (m,1H),3.64 (m, 1H), 3.30 (m, 5H), 2.40 (m, 1H), 1.90 (m, 5H); MS (EI) m/z 271(M⁺+1).

Example 89N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)benzothiazole-7-carboxamidehydrochloride

[0772] 1,3-Benzothiazole-7-carboxylic acid.

[0773] Prepared from ethyl 3-aminobenzoate using Procedure P. Yield 2.75g (91%). 1H NMR (500 MHz, DMSO-d₆) δ 7.71 (t, J=7.5, 1H), 8.15 (d, J=7,1H), 8.38 (d, J=8, 1H), 9.51 (s, 1H), 13.74 (bs, 1H); MS (APCI) m/z 178(M⁺−1).

[0774] N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-7-carboxamidehydrochloride.

[0775] Prepared from 1,3-benzothiazole-7-carboxylic acid using ProcedureC. ¹H NMR (500 MHz, DMSO-d₆) δ 1.71-1.75 (m, 1H), 1.92-1.96 (m, 2H),2.18-2.26 (m, 2H), 3.17-3.25 (m, 3H), 3.45-3.66 (m, 3H), 4.44 (d, J=6,1H), 7.69 (t, J=8, 1H), 8.28 (d, J=8, 1H), 8.54 (d, J=8, 1H), 9.37 (d,J=6.5, 1H), 9.49 (s, 1H), 10.88 (bs, 1H); MS (EI) m/z 288 (M⁺+1).

Example 90N-((3S)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-7-carboxamidehydrochloride

[0776]

[0777] Prepared from 1,3-benzothiazole-7-carboxylic acid using ProcedureC. 1H NMR (500 MHz, DMSO-d₆) δ 1.71-1.75 (m, 1H), 1.92-1.95 (m, 2H),2.17-2.26 (m, 2H), 3.17-3.24 (m, 3H), 3.44-3.55 (m, 2H), 3.60-3.65 (m,1H), 4.44 (d, J=6, 1H), 7.69 (t, J=8, 1H), 8.29 (d, J=8, 1H), 8.53 (d,J=8, 1H), 9.36 (d, J=6.5, 1H), 9.48 (s, 1H), 10.87 (bs, 2H); MS (EI) m/z288 (M⁺+1).

Example 91N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamide

[0778] 1H-Indazole-7-carboxylic acid

[0779] Prepared from 2-amino-3-methylbenzoic acid using procedure M.Yield 5.86 g (94%). 1H NMR (500 MHz, DMSO-d₆) δ 13.20 (bs, 2H), 8.23 (s,1H), 8.08 (dd, 1H), 8.00 (dd, 1H), 7.25 (dd, 1H); MS (APCI) m/z 161 (M+-1).

[0780] N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamide.

[0781] Prepared from 1H-indazole-7-carboxylic acid using Procedure A.Yield 50%. 1H NMR (CD₃OD) δ 8.15 (s, 1H), 7.97 (dd, J=7.5, 7.8, 2H),7.21 (dd, J=7.8, 7.5, 1H), 4.30 (m, 1H), 3.43 (m, 1H), 3.06 (m,1H), 2.85(m, 4H), 1.95 (m, 5H); MS (EI) m/z 271(M⁺+1).

Example 92N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamidehydrochloride

[0782]

[0783] Prepared from1H-indazole-7-carboxylic acid using Procedure C.Yield 71%. 1H NMR (500 MHz, CD₃OD) δ 8.61 (s, 1H), 8.32 (d, J=7.5, 1H),8.14 (d, J=8.0, 1H), 7.44 (dd, J =8.0, 7.5, 1H), 4.59 (m, 1H), 3.89 (m,1H), 3.55 (m, 1H), 3.40 (m, 4H), 2.44 (m, 1H), 2.30 (m, 1H), 2.12 (m,2H), 1.96 (m, 1H); MS (APCI) m/z 271 (M⁺+1).

Example 93 N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl-1H-indazole-7-carboxamide

[0784]

[0785] Prepared from 1H-indazole-7-carboxylic acid using Procedure A.Yield 50%. 1H NMR (CD₃OD) δ 8.16 (s, 1H), 8.05 (dd, J=6.6, 0.9, 1H),7.21 (dd, J=0.9, 7.5, 1H), 7.21 (dd, J=7.5, 6.6, 1H), 4.48 (m, 1H), 3.62(m, 1H), 3.20 (m,1H), 3.10 (m, 4H), 1.95 (m, 5H); MS (EI) m/z 271(M⁺+1).

Example 94N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamidehydrochloride

[0786]

[0787] Prepared from1H-indazole-7-carboxylic acid using Procedure C.Yield 71%. 1H NMR (500 MHz, CD₃OD) δ 8.61 (s, 1H), 8.32 (d, J=7.5, 1H),8.14 (d, J=8.0, 1H), 7.44 (t, J =8.0, 1H), 4.59 (m, 1H), 3.89 (m, 1H),3.55 (m, 1H), 3.40 (m, 4H), 2.44 (m, 1H), 2.30 (m, 1H), 2.12 (m, 2H),1.96 (m, 1H); MS (APCI) m/z 271 (M⁺+1); m.p. 180-188° C.

Example 95 [³H] MLA binding

[0788] Materials:

[0789] Rat Brain: Pel-Freez Biologicals, CAT No. 56004-2

[0790] Protease inhibitor cocktail tablet: Roche, CAT No. 1697498

[0791] Membrane preparation

[0792] Rat brains in 20 vol (w/v) of ice-cold 0.32 M sucrose withprotease inhibitors (one tablet per 50 ml,) were homogenized with apolytron for 10 sec at setting 11, then centrifuged 10 min at 1000 g, 4°C. The supernatant was centrifuged again for 20 min at 20,000 g, 4° C.The pellets were resuspended in binding buffer (200 mM TRIS-HCl, 20 mMHEPES, pH 7.5, 144 mM NaCl, 1.5 mM KCl, 1 mM MgSO₄, 2 mM CaCl₂, 0.1%(w/v) BSA) and stored membrane prep at -80° C.

[0793] For saturation assay, the 200 μl assay mixture in binding buffercontains 200 μg of membrane protein, 0.2 to 44 nM of [³H] MLA. Thenonspecific binding was defined using 1 μM MLA. Competition assay wascarried out with 2 nM [³H] MLA and a desirable range of compounds. Theassay mixture was incubated at 22° C. for 2 hours, then harvested withGF/B filter presoaked with 0.3% PEI in binding buffer using Tomtecharvester. The filter was washed three time with binding buffer and theradioactivity was counted with Trilux.

[0794] The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

[0795] While the invention has been illustrated with respect to theproduction and of particular compounds, it is apparent that variationsand modifications of the invention can be made without departing fromthe spirit or scope of the invention.

We claim:
 1. A compound of Formulas I, II, III, or IV:

wherein A is an indazolyl, benzothiazolyl, or isobenzothiazolyl groupaccording to subformulas (a) to (c), respectively,

X is O or S; R¹ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms,cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7carbon atoms, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having 3 to7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthiohaving 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4 carbonatoms, hydoxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Ar orHet; R² is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms; R³ is H, F,Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1 to 4 carbon atoms,fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms,cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydoxyalkylhaving 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms,monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein eachalkyl group independently has 1 to 4 carbon atoms, Ar or Het; R⁴ is H,F, Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1 to 4 carbon atoms,fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms,cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydoxyalkylhaving 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms,monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein eachalkyl group independently has 1 to 4 carbon atoms, Ar or Het; R⁵ is H,F, Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1 to 4 carbon atoms,fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms,cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4carbon atoms, fluorinated alkoxy having 1 to 4 carbon atoms, hydoxyalkylhaving 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms,monoalkylamino having 1 to 4 carbon atoms, dialkylamino wherein eachalkyl group independently has 1 to 4 carbon atoms, Ar or Het; Ar is anaryl group containing 6 to 10 carbon atoms which is unsubstituted orsubstituted one or more times by alkyl having 1 to 8 C atoms, alkoxyhaving 1 to 8 C atoms, halogen, dialkylamino wherein the alkyl portionseach have 1 to 8 C atoms, amino, cyano, hydroxyl, nitro, halogenatedalkyl having 1 to 8 C atoms, halogenated alkoxy having 1 to 8 C atoms,hydroxyalkyl having 1 to 8 C atoms, hydroxyalkoxy having 2 to 8 C atoms,alkenyloxy having 3 to 8 C atoms, alkylthio having 1 to 8 C atoms,alkylsulphinyl having 1 to 8 C atoms, alkylsulphonyl having 1 to 8 Catoms, monoalkylamino having 1 to 8 C atoms, cycloalkylamino wherein thecycloalkyl group has 3 to 7 C atoms and is optionally substituted,aryloxy wherein the aryl portion contains 6 to 10 carbon atoms and isoptionally substituted, arylthio wherein the aryl portion contains 6 to10 carbon atoms and is optionally substituted, cycloalkyloxy wherein thecycloalkyl group has 3 to 7 C atoms and is optionally substituted,sulfo, sulfonylamino, acylamido, acyloxy or combinations thereof; andHet is a heterocyclic group, which is fully saturated, partiallysaturated or fully unsaturated, having 5 to 10 ring atoms in which atleast 1 ring atom is a N, O or S atom, which is unsubstituted orsubstituted one or more times by halogen, aryl having 6 to 10 carbonatoms and is optionally substituted, alkyl having 1 to 8 C atoms, alkoxyhaving 1 to 8 C atoms, cyano, trifluoromethyl, nitro, oxo, amino,monoalkylamino having 1 to 8 C atoms, dialkylamino wherein each alkylgroup has 1 to 8 C atoms, or combinations thereof; or a pharmaceuticallyacceptable salt thereof, wherein when said compound is of Formula I theindazolyl group of group A is attached via its 3, 4, or 7 position, thebenzothiazolyl group of group A is attached via its 4 or 7 position, orthe isobenzothiazolyl group of group A is attached via its 3, 4, or 7position.
 2. A compound according to claim 1, wherein said compound isof formulas Ia, Ib, Ie, If, Ii, Ij, Ik, or Io:


3. A compound according to claim 1, wherein said compound is of formulaIIa to IIo:


4. A compound according to claim 1, wherein said compound is of formulaIIIa to IIIo:


5. A compound according to claim 1, wherein said compound is of formulaIVa to IVo:


6. A compound according to Formulae I′-IV′:

wherein A is an indazolyl or benzothiazolyl according to subformulas (a)to (b), respectively,

R¹ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1 to 4 carbonatoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkyl having 3to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, alkoxyhaving 1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms,alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1 to 4carbon atoms, hydoxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyhaving 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms,dialkylamino wherein each alkyl group independently has 1 to 4 carbonatoms, Ar or Het; R² is H, alkyl having 1 to 4 carbon atoms, cycloalkylhaving 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbonatoms; R³ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1 to 4carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, cycloalkylhaving 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms,alkoxy having 1 to 4 carbon atoms, cycloalkoxy having 3 to 7 carbonatoms, alkylthio having 1 to 4 carbon atoms, fluorinated alkoxy having 1to 4 carbon atoms, hydoxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxyhaving 2 to 4 carbon atoms, monoalkylamino having 1 to 4 carbon atoms,dialkylamino wherein each alkyl group independently has 1 to 4 carbonatoms, Ar or Het; Ar is an aryl group containing 6 to 10 carbon atomswhich is unsubstituted or substituted one or more times by alkyl having1 to 8 C atoms, alkoxy having 1 to 8 C atoms, halogen, dialkylaminowherein the alkyl portions each have 1 to 8 C atoms, amino, cyano,hydroxyl, nitro, halogenated alkyl having 1 to 8 C atoms, halogenatedalkoxy having 1 to 8 C atoms, hydroxyalkyl having 1 to 8 C atoms,hydroxyalkoxy having 2 to 8 C atoms, alkenyloxy having 3 to 8 C atoms,alkylthio having 1 to 8 C atoms, alkylsulphinyl having 1 to 8 C atoms,alkylsulphonyl having 1 to 8 C atoms, monoalkylamino having 1 to 8 Catoms, cycloalkylamino wherein the cycloalkyl group has 3 to 7 C atomsand is optionally substituted, aryloxy wherein the aryl portion contains6 to 10 carbon atoms and is optionally substituted, arylthio wherein thearyl portion contains 6 to 10 carbon atoms and is optionallysubstituted, cycloalkyloxy wherein the cycloalkyl group has 3 to 7 Catoms and is optionally substituted, sulfo, sulfonylamino, acylamido,acyloxy or combinations thereof; and Het is a heterocyclic group, whichis fully saturated, partially saturated or fully unsaturated, having 5to 10 ring atoms in which at least 1 ring atom is a N, O or S atom,which is unsubstituted or substituted one or more times by halogen, arylhaving 6 to 10 carbon atoms and is optionally substituted, alkyl having1 to 8 C atoms, alkoxy having 1 to 8 C atoms, cyano, trifluoromethyl,nitro, oxo, amino, monoalkylamino having 1 to 8 C atoms, dialkylaminowherein each alkyl group has 1 to 8 C atoms, or combinations thereof; ora pharmaceutically acceptable salt thereof.
 7. A compound according toclaim 6, wherein said compound is of formula I′a, Ib, Ie, If, to Ii:


8. A compound according to claim 6, wherein said compound is of formulaII′a to II′i:


9. A compound according to claim 6, wherein said compound is of formulaIII′a to III″i:


10. A compound according to claim 6, wherein said compound is of formulaIV′a to IV′i:


11. A compound according to any one of claims 1 to 10, wherein R¹ is H,F, Cl, Br, 2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl.
 12. Acompound according to any one of claims 1 to 11, wherein R² is H,methyl, 2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl.
 13. A compoundaccording to any one of claims 1 to 12, wherein R³ is H, F, Cl, Br,2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl. 14 compound according toany one of claims 1 to 13, wherein R¹ is H, F, Cl, Br, methyl, methoxy,or amino.
 15. A compound according to any one of claims 1 to 14, whereinR² is H or methyl.
 16. A compound according to any one of claims 1 to15, wherein, and R³ is H, F, Cl, Br, methyl, methoxy, or amino.
 17. Acompound according to any one of claims 1 to 5, wherein R⁴ is H, F, Cl,Br, 2-thiophenyl, 3-thiophenyl, 3-furyl, phenyl, or methoxy.
 18. Acompound according to any one of claims 1 to 5 and 17, wherein R⁵ is H.19. A compound according to claim 17, wherein R¹ is H, F, Cl, Br,2-thiophenyl, 3-thiophenyl, 3-fuiryl, or phenyl, R² is H, methyl,2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl, and R³ is H, F, Cl, Br,2-thiophenyl, 3-thiophenyl, 3-furyl, or phenyl.
 20. A compound accordingto claim 18, wherein R¹ is H, F, Cl, Br, 2-thiophenyl, 3-thiophenyl,3-fuiryl, or phenyl, R² is H, methyl, 2-thiophenyl, 3-thiophenyl,3-fuiryl, or phenyl, and R³ is H, F, Cl, Br, 2-thiophenyl, 3-thiophenyl,3-furyl, or phenyl.
 21. A compound according to claim 1, wherein saidcompound is selected from:N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamnidehydrochloride,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)benzo[d]isothiazole-3-carboxamidehydrochloride,N-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide,N-(-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamidehydrochloride,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamidehydrochloride,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamidehydrochloride, 1-Methyl-1H-Indazole-3-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl, (R) 1-Methyl-1H-Indazole-3-carboxamide,N-1 -aza-bicyclo[2,2,2]oct-3-yl, (S) 1-Methyl-1H-Indazole-3-carboxamide,N-1 -aza-bicyclo[2,2,2]oct-3-yl,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(methoxy)benzo[d]isothiazole-3-carboxamide hydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(cyclopropyl)-1H-indazole-3-carboxamidehydroformate, N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamidehydroformate, N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzo[d]isothiazole-3-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-methoxybenzo[d]isothiazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(bromo)-1H-indazole-3-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(furan-3-yl)-1H-indazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(phenyl)-1H-indazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-5-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-cyclopropylbenzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo[d]isothiazole-3-carboxamnidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-furan-3-yl)benzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-furan-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxybenzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(morpholin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-³-yl)-⁶-(pyridin-4-yl)benzo[d]isothiazole-3-carboxaniidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)benzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)benzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(bromo)-1H-indazole-3-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)-1H-indazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxanidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-bromobenzo[d]isothiazole-3-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-cyclopropylbenzo[d]isothiazole-3-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(2-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate, N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(3-fluorophenyl)benzo [d]isothiazole-3-carboxamide hydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(4-fluorophenyl)benzo[d]isothiazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxybenzo[d]isothiazole-3-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(morpholin-4-yl)benzo[d]isothiazole-3-carboxamnidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-phenylbenzo[d]isothiazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-³-yl)-6-(pyridin-3-yl)benzo[d]isothiazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(pyridin-4-yl)benzo[d]isothiazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)benzo[d]isothiazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)benzo[d]isothiazole-3-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(bromo)-1H-indazole-3-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(furan-3-yl)-1H-indazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(phenyl)-1H-indazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-2-yl)-1H-indazole-3-carboxamidehydroformate,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-6-(thiophen-3-yl)-1H-indazole-3-carboxamidehydroformate,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-7-methoxybenzo[d]isothiazole-3-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-7-methoxybenzo[d]isothiazole-3-carboxamide,N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)-N-(1H-indazol-3-ylmethyl)amine,N-((3S)-1-Aza-bicyclo[2,2,2]oct-3-yl)-N-(1H-indazol-3-ylmethyl)amine,N-((3R)-1-Aza-bicyclo[2.2.2]oct-3-yl)benzothiazole-4-carboxamidedihydrochloride,N-((3S)-1-Aza-bicyclo[2.2.2]oct-3-yl)benzothiazole-4-carboxamidedihydrochloride,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-4-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-4-carboxamide,N-(1H-Indazol-4-yl)-1 -azabicyclo[2,2,2]oct-3-ylcarboxamide,N-(1-Azabicyclo[2,2,2]oct-3-yl)-N-(iH-indazol-4-ylmethyl)amine,N-((3R)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-7-carboxamidehydrochloride,N-((3S)-1-Azabicyclo[2,2,2]oct-3-yl)benzothiazole-7-carboxamidehydrochloride,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamide,N-((3R)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamidehydrochloride,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamide,N-((3S)-1-Azabicyclo[2.2.2]oct-3-yl)-1H-indazole-7-carboxamidehydrochloride, Benzothiazole-4-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl, (R) Benzothiazole-4-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl, (S) Benzothiazole-4-carboxamide,N-1-aza-bicyclo[2,2,2]oct-3-yl, 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,N-1H-indazol-3-yl, (S) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,N-1H-indazol-3-yl, (R) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,N-1H-indazol-3-yl, (S) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,N-1H-indazol-4-yl, (R) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,N-1H-indazol-4-yl, 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,N-1H-indazol-7-yl, (S) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamnide,N-1H-indazol-7-yl, (R) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,N-1H-indazol-7-yl, 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,benzothiazol-4-yl, (S) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,benzothiazol-4-yl, (R) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,benzothiazol-4-yl, 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,benzothiazol-7-yl, (S) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxamide,benzothiazol-7-yl, (R) 1-Aza-bicyclo[2,2,2]oct-3-ylcarboxaniide,benzothiazol-7-yl, (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-3-ylmethyl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-3-ylmethyl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-4-ylmethyl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-4-ylmethyl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-5-ylmethyl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-5-ylmethyl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-5-ylmethyl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-6-ylmethyl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-6-ylmethyl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-6-ylmethyl)-amine, (1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-7-ylmethyl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(1H-indazol-7-ylmethyl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3 -yl)-(1H-indazol-7-ylmethyl)-amiine,(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-4-ylmethyl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-4-ylmethyl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-4-ylmethyl)-amine,(1-Aza-bicyclo[2,2,2]oct-³-yl)-(benzothiazol-5-ylmethyl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-5-ylmethyl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-5-ylmethyl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-6-ylmethyl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-6-ylmethyl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-6-ylmethyl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-7-ylmethyl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-7-ylmethyl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-yl)-(benzothiazol-7-ylmethyl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-3-yl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-3-yl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3 -ylmethyl)-(1H-indazol-3-yl)-amine,(1-Aza-bicyclo [2,2,2]oct-3-ylmethyl)-(1H-indazol-4-yl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(H-indazol-4-yl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-4-yl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-5-yl)-amine, (S)(1-Aza-bicyclo[2,2,2] oct-3-ylmethyl)-(1H-indazol-5-yl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-5-yl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-6-yl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-6-yl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-6-yl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-7-yl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(1H-indazol-7-yl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3 -ylmethyl)-(1H-indazol-7-yl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-4-yl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-4-yl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-4-yl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-5-yl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-5-yl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-5-yl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-6-yl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-6-yl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-6-yl)-amine,(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-7-yl)-amine, (S)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-7-yl)-amine, (R)(1-Aza-bicyclo[2,2,2]oct-3-ylmethyl)-(benzothiazol-7-yl)-amine, andphysiological salts thereof.
 22. A pharmaceutical composition comprisinga compound according to any one of claims 1 to 21 and a pharmaceuticallyacceptable carrier.
 23. A method of selectively activating/stimulatingα-7 nicotinic receptors in a mammal wherein such activation/stimulationhas a therapeutic effect, comprising administering to an animal in needthereof an effective amount of a compound according to any one of claims1 to
 21. 24. A method of treating a patient suffering from psychoticdiseases, neurodegenerative diseases involving a dysfumction of thecholinergic system, and conditions of memory and/or cognition impairmentcomprising administering to the patient an effective amount of acompound according to any one of claims 1 to
 21. 25. A method oftreating a patient suffering from dementia and other conditions withmemory loss comprising administering to the patient an effective amountof a compound according to any one of claims 1 to
 21. 26. A method oftreating a patient suffering from memory impairment due to mildcognitive impairment due to aging, Alzheimer's disease, schizophrenia,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNShypoxia, cerebral senility, or multiinfarct dementia comprisingadministering an effective amount of a compound according according toany one of claims 1 to
 21. 27. A method of treating and/or preventingdementia in an Alzheimer's patient comprising administering to thepatient a therapeutically effective amount of a compound according toany one of claims 1 to 21 to inhibit the binding of an amyloid betapeptide with nAChRs.
 28. A method of treating a patient for alcoholwithdrawal or treating a patient with anti-intoxication therapycomprising administering to the patient an effective amount of acompound according to any one of claims 1 to
 21. 29. A method oftreating a patient to provide for neuroprotection against damageassociated with strokes and ischemia and glutamate-inducedexcitotoxicity comprising administering to the patient an effectiveamount of a compound according to anyone of claims 1 to
 21. 30. A methodof treating a patient suffering from nicotine addiction, pain, jetlag,obesity and/or diabetes, or a method of inducing smoking cessation in apatient comprising administering to the patient an effective amount of acompound according to any one of claims 1 to
 21. 31. A method oftreating a patient suffering from mild cognitive impairment (MCI),vascular dementia (VaD), age-associated cognitive decline (AACD),amnesia associated with open-heart-surgery, cardiac arrest, generalanesthesia, memory deficits from exposure to anesthetic agents, sleepdeprivation induced cognitive impairment, chronic fatigue syndrome,narcolepsy, AIDS-related dementia, epilepsy-related cognitiveimpairment, Down's syndrome, Alcoholism related dementia, drug/substanceinduced memory impairments, Dementia Puglistica (Boxer Syndrome), oranimal dementia comprising administering to the patient an effectiveamount of a compound according to any one of claims 1 to
 21. 32. Amethod of treating a patient suffering from a disease state involvingdecreased nicotinic acetylcholine receptor activity comprisingadministering to the patient an effective amount of a compound accordingto any one of claims 1 to
 21. 33. A method for the treatment orprophylaxis of a disease or condition resulting from dysfunction ofnicotinic acetylcholine receptor transmission in a mammal comprisingadministering to the mammal an effective amount of a compound accordingto any one of claims 1 to
 21. 34. A method for the treatment orprophylaxis of a disease or condition resulting from defective ormalfunctioning nicotinic acetylcholine receptors in a mammal comprisingadministering to the mammal an effective amount of a compound accordingto any one of claims 1 to
 21. 35. A method for the treatment orprophylaxis of a disease or condition resulting from suppressednicotinic acetylcholine receptor transmission in a mammal comprisingadministering to the mammal an effective amount of a compound accordingto any one of claims 1 to
 21. 36. A method for the treatment orprophylaxis of a disease or condition resulting from loss of cholinergicsynapses in a manmmal comprising administering to the mammal aneffective amount of a compound according to any one of claims 1 to 21.